Abstract
DExD/H-box RNA helicases constitute one of the largest families of adenosine triphosphate (ATP)-dependent nucleic-acid enzymes, with roles spanning the full breadth of RNA metabolism, from transcription to turnover. Their defining architectural feature is a conserved helicase core comprising two tandem RecA-like domains that couples ATP hydrolysis to duplex unwinding and ribonucleoprotein remodeling. Structural investigations have historically focused on human and yeast model systems, but recent methodological advances, particularly cryo-electron microscopy and deep learning-based structure prediction, have broadened the structural coverage of the DDX family, including full-length constructs and their incorporation into multiprotein assemblies. In plants, DDX helicases remain far less characterized despite their essential functions in development and stress adaptation. This review integrates structural biology insights with recent multi-omics datasets from cold-stressed rubber tree (Hevea brasiliensis), a tropical crop highly susceptible to chilling injury. Quantitative profiling has identified nine differentially abundant DDX proteins under cold stress, among which DDX39B shows the most pronounced response. Rubber tree DDX39B shares >95% sequence identity with orthologs from other tropical species and ~73% identity with human DDX39B; AlphaFold2 predictions reveal near-identical core helicase folds, consistent with strong functional constraint across vast evolutionary distances. These predictions also reveal plant-specific domain arrangements, including a putative DDX39B isoform bearing additional LysM and protein kinase domains. This work illustrates how computational structure prediction can bridge the sequence-to-function gap for stress-responsive proteins in non-model plant species and provides a conceptual framework for dissecting DDX helicase roles in plant abiotic stress tolerance.
1 Introduction
RNA helicases form a vast superfamily of motor proteins that harness the chemical energy of ATP binding and hydrolysis to remodel RNA secondary structures, disassemble ribonucleoprotein (RNP) complexes, and drive conformational rearrangements of RNA molecules (Shi et al., 2004; Fairman-Williams et al., 2010; Su et al., 2021; Gao et al., 2022). Within this superfamily, the DEAD-box (DDX) family stands out: named for its signature Asp-Glu-Ala-Asp (DEAD) sequence in Walker B motif II, it is the largest and most thoroughly characterized group of RNA helicases (He et al., 2026; Hohmann et al., 2026). The architectural hallmark of DDX proteins is a conserved helicase core of two RecA-like domains (D1 and D2) that together contain at least twelve conserved sequence motifs involved in ATP coordination, RNA substrate recognition, and interdomain communication (Bai et al., 2021; Devasahayam Arokia Balaya et al., 2025; Bugai et al., 2026; Hia et al., 2026). Structural studies, from early X-ray crystallography to recent cryo-EM and AlphaFold2 predictions, have progressively unveiled the conformational dynamics and regulatory mechanisms of DDX helicases (Yin et al., 2015; Studer et al., 2020; Bugai et al., 2026).
Most DDX helicase research has focused on human and yeast model systems, but evidence indicates that DDX proteins play equally critical roles in plants, where they contribute to developmental patterning, hormone signaling, and responses to both abiotic and biotic stresses (Linder and Owttrim, 2009; Huang et al., 2016; Capel et al., 2020; He et al., 2021; Jia et al., 2025). In Arabidopsis thaliana, for example, the DEAD-box helicase AtRH7/PRH75 participates in pre-rRNA processing and is required for cold tolerance (Huang et al., 2016), whereas DDX42 plays a critical role in pre-mRNA splicing under cold stress (Lu et al., 2020). More recently, an RNA helicase was shown to coordinate with iron signal regulators to alleviate chilling stress in A. thaliana (Xing et al., 2025). These studies establish that DEAD-box helicases are integral components of the plant cold-stress response network, yet their roles in tropical crop species remain largely unexplored.
Rubber tree (Hevea brasiliensis) is the world’s primary commercial source of natural rubber, a strategically vital industrial material with applications spanning the automotive, medical, and defense sectors (Tang et al., 2016; Liu et al., 2020; Chao et al., 2023; Niu et al., 2024). Native to the Amazon basin, rubber tree has evolved under warm and stable climatic conditions, rendering it highly susceptible to cold stress, a major environmental constraint that restricts its cultivation range and suppresses latex yield during cold spells (Sullivan et al., 2020; Gao et al., 2025; Wang et al., 2026). Commercially, rubber is cultivated primarily in Southeast Asia (Thailand, Indonesia, Vietnam, Malaysia), West Africa (Côte d’Ivoire, Nigeria, Liberia), and southern China (Yunnan, Hainan, Guangdong). In many of these regions, periodic cold fronts, particularly in the northern cultivation margins such as Yunnan Province in China and the highlands of mainland Southeast Asia, cause chilling injury, defoliation, and significant reductions in latex production (Tang et al., 2016; Liu et al., 2020). The economic impact is substantial: cold events can reduce annual rubber output by 10 to 30% in affected areas and limit the expansion of rubber cultivation into marginally suitable lands that could otherwise support smallholder livelihoods. Elucidating the molecular mechanisms underlying cold stress tolerance in the rubber tree is therefore of both fundamental biological significance and practical agricultural importance.
Recent multi-omics investigations have identified multiple DDX family proteins that are differentially abundant under cold stress in rubber tree, suggesting that DDX-mediated reprogramming of RNA metabolism constitutes an important component of the cold stress response (Mao et al., 2022; Gao et al., 2025). In this review, we synthesize current structural understanding of the DEAD-box helicase family, integrate recent proteomic evidence from cold-stressed rubber tree, and use AlphaFold2 structural prediction to examine the cold-responsive helicase DDX39B in detail. We further discuss the potential translational implications of these findings for rubber-tree improvement and cold-tolerance breeding.
2 Classification and structural framework of DEAD-box helicases
DEAD-box proteins belong to helicase superfamily 2 (SF2), one of the largest and most diverse helicase superfamilies (Fairman-Williams et al., 2010). Within SF2, the DExD/H-box helicases form a major subdivision that is further divided into two principal clades: the DEAD-box (DDX) family and the DEAH/RHA family. These clades are distinguished by the sequence of their Walker B motif II, DEAD (Asp-Glu-Ala-Asp) for DDX proteins and DEAH (Asp-Glu-Ala-His) for DEAH/RHA proteins, and by differences in their mechanistic properties and domain architectures (Figure 1A). Representative members of the DEAD-box family include DDX3X, DDX21, DDX39B/UAP56, eukaryotic initiation factor 4A (eIF4A), and DDX58/retinoic acid-inducible gene I (RIG-I), whereas DHX36, DHX9, and BRR2 exemplify the DEAH/RHA family. Throughout this review, we use “DEAD-box” or “DDX” to refer specifically to the DEAD-box clade and “DExD/H-box” when discussing the broader subdivision encompassing both clades.
Figure 1
The defining architectural feature of DEAD-box helicases is a conserved catalytic core of two RecA-like domains (D1 and D2) that jointly coordinate ATP hydrolysis and RNA substrate recognition (Figure 1B). Twelve signature sequence motifs map to these two domains; some are shared broadly across SF2, whereas others, most notably the eponymous Asp-Glu-Ala-Asp (DEAD) sequence in motif II, are unique identifiers of the DEAD-box clade (Figure 1C). Variable N- and C-terminal extensions flank the core and underpin the family’s wide range of substrate specificities and biological functions (Cordin et al., 2006).
DEAD-box helicases operate via a cyclic series of conformational rearrangements. When unbound to RNA, the two RecA-like domains exhibit a range of open conformations and weak RNA-binding activity (Figure 1D). Engagement of dsRNA, coupled with ATP binding, drives closure of the interdomain cleft, generating a compact ternary complex that strains and unwinds the duplex. Hydrolysis of ATP then weakens the interdomain interface, promoting release of the unwound RNA strand and ADP-Pi products, and resetting the enzyme for subsequent catalytic rounds.
Table 1 summarizes the structural data for DEAD-box family proteins curated from the Protein Data Bank in Europe (https://www.ebi.ac.uk/pdbe/). A striking pattern emerges from this data. Only a handful of full-length DDX proteins have been structurally characterized, including DDX2A and DDX8 (Napetschnig et al., 2009; Parsyan et al., 2011). The available structures, by contrast, represent truncated constructs encompassing primarily the helicase core. Many DDX structures have been determined in complex with binding partners, predominantly RNA-protein and protein-protein complexes. In recent years, cryo-electron microscopy has changed the landscape, facilitating structural analysis of an increasing number of full-length DDX family proteins involved in mRNA splicing, including DDX37, DDX38, and DDX46 (Yang et al., 2023; Liao et al., 2024; Hernández-Reyes et al., 2025).
Table 1
| Gene | Expression system | Sequence | Method | PDB ID | Ref. |
|---|---|---|---|---|---|
| DDX1 | E. coli | 72-283 | X-ray | 4XW3 | 2015 (Kellner and Meinhart, 2015) |
| DDX2A | E. coli | 20-406 | X-ray | 2ZU6 | 2009 (Loh et al., 2009) |
| DDX2A | E. coli | 1-406 | cryo-EM | 6ZMW | 2020 (Brito Querido et al., 2020) |
| DDX2B | E. coli | 22-240 | X-ray | 3BOR | 2010 (Schütz et al., 2010) |
| DDX3X | E. coli | 132-607 | X-ray | 6O5F | 2019 (Song and Ji, 2019) |
| DDX4 | E. coli | 228-247 | X-ray | 5JIU | 2016 (Hong et al., 2016) |
| DDX5 | E. coli | 52-304 | X-ray | 4A4D | 2012 (Dutta et al., 2012) |
| DDX6 | E. coli | 95-469 | X-ray | 5ANR | 2015 (Ozgur et al., 2015) |
| DDX6 | E. coli | 295-483 | X-ray | 6S8S | 2019 (Peter et al., 2019) |
| DDX8 | HeLa | 1-1220 | cryo-EM | 6ICZ | 2019 (Zhang et al., 2019) |
| DDX9 | E. coli | 1-91 | X-ray | 3VYY | 2013 (Fu and Yuan, 2013) |
| DDX9 | E. coli | 152-264 | X-ray | 3VYX | 2013 (Fu and Yuan, 2013) |
| DDX9 | E. coli | 329-563 | X-ray | 3LLM | 2010 (Schütz et al., 2010) |
| DDX10 | E. coli | 47-280 | X-ray | 2PL3 | 2010 (Schütz et al., 2010) |
| DDX13 | Insect cells | 1-1246 | cryo-EM | 7QDR | 2022 (Kögel et al., 2022) |
| DDX15 | Sf9 cells | 110-795 | X-ray | 5XDR | 2017 (Murakami et al., 2017) |
| DDX15 | E. coli | 113-795 | X-ray | 6SHS | 2020 (Studer et al., 2020) |
| DDX16 | Insect cells | 1-1041 | cryo-EM | 7DVQ | 2021 (Bai et al., 2021) |
| DDX17 | E. coli | 32-477 | X-ray | 6UV3 | 2019 (Ngo et al., 2019) |
| DDX18 | E. coli | 149-387 | X-ray | 3LY5 | 2010 (Schütz et al., 2010) |
| DDX19B | E. coli | 54-479 | X-ray | 6B4K | 2018 (Lin et al., 2018) |
| DDX19B | E. coli | 1-300 | X-ray | 3FMO | 2009 (Napetschnig et al., 2009) |
| DDX20 | E. coli | 22-240 | X-ray | 3B7G | 2010 (Schütz et al., 2010) |
| DDX21 | E. coli | 188-563 | X-ray | 6L5O | 2020 (Chen et al., 2020) |
| DDX21 | E. coli | 617-710 | NMR | 2M3D | |
| DDX23 | E. coli | 338-820 | X-ray | 4NH0 | 2014 (Möhlmann et al., 2014) |
| DDX23 | Saccharomyces cerevisiae | 1-820 | cryo-EM | 6QW6 | 2019 (Charenton et al., 2019) |
| DDX25 | E. coli | 307-479 | X-ray | 2RB4 | 2010 (Schütz et al., 2010) |
| DDX26 | E. coli | 800-887 | X-ray | 7BV7 | 2021 (Jia et al., 2021) |
| DDX26 | HEK Expi293 cells | 1-887 | cryo-EM | 7CUN | 2020 (Zheng et al., 2020) |
| DDX28 | HEK Flp-In 293 T-Rex cells | 1-540 | cryo-EM | 7OI6 | 2021 (Cheng et al., 2021) |
| DDX30 | E. coli | 42-147 | NMR | 2DB2 | |
| DDX36 | E. coli | 53–70 | NMR | 2N16 | 2015 (Heddi et al., 2015) |
| DDX36 | E. coli | 53-81 | X-ray | 6Q6R | 2020 (Heddi et al., 2020) |
| DDX37 | HEK Expi293 cells | 1-1157 | cryo-EM | 7MQA | 2021 (Singh et al., 2021) |
| DDX38 | E. coli | 1-1227 | cryo-EM | 6ZYM | 2020 (Bertram et al., 2020) |
| DDX39B | E. coli | 1-428 | cryo-EM | 7APK | 2020 (Pühringer et al., 2020) |
| DDX39B | E. coli | 45-428 | X-ray | 1XTK | 2004 (Shi et al., 2004) |
| DDX41 | E. coli | 153-410 | X-ray | 5H1Y | 2017 (Jiang et al., 2017) |
| DDX41 | E. coli | 402-569 | X-ray | 2P6N | 2010 (Schütz et al., 2010) |
| DDX46 | HeLa S3 cells | 1-1031 | cryo-EM | 6Y50 | 2020 (Zhang et al., 2020) |
| DDX47 | E. coli | 5-230 | X-ray | 3BER | 2010 (Schütz et al., 2010) |
| DDX48 | E. coli | 1-411 | X-ray | 4C9B | 2013 (Buchwald et al., 2013) |
| DDX50 | Synthesis system | 575-659 | NMR | 2E29 | 2009 (Ohnishi et al., 2009) |
| DDX52 | E. coli | 139-381 | X-ray | 3DKP | 2010 (Schütz et al., 2010) |
| DDX53 | E. coli | 204-430 | X-ray | 3IUY | 2010 (Schütz et al., 2010) |
| DDX58 | E. coli | 230-925 | X-ray | 2YKG | 2011 (Luo et al., 2011) |
| DDX58 | E. coli | 1-201 | X-ray | 4P4H | 2014 (Wu et al., 2014) |
| DDX59 | Synthesis system | 94-146 | NMR | 2YQP |
Reported DEAD-box family proteins with available structures.
This table includes Homo sapiens proteins only. For the same protein with multiple structures, only representative data are shown. Data curated from the Protein Data Bank in Europe (https://www.ebi.ac.uk/pdbe/).
3 Structural features and functional diversity of representative DEAD-box helicases
In this section, we review the structural basis and functional diversity of representative DEAD-box and related DExD/H-box helicases. These examples, drawn primarily from human and animal systems where structural data are most abundant, illustrate the mechanistic paradigms that inform our understanding of plant homologs.
3.1 DDX3X: a prototypical DEAD-box helicase in RNA metabolism
DDX3X is a prototypical DEAD-box helicase that functions as a key regulator of RNA metabolism (Mo et al., 2021; Cai et al., 2025; Zhang et al., 2024). The human genome encodes two DDX3 paralogs, DDX3X and DDX3Y, sharing 92% sequence identity but differing markedly in expression: DDX3X is ubiquitously expressed across tissues, whereas DDX3Y is testis-restricted and required for spermatogenesis (You et al., 2023; Wang et al., 2025). DDX3X orthologs are deeply conserved across eukaryotes, consistent with their fundamental roles in RNA processing (Gadek et al., 2023; Ma et al., 2025). DDX3X participates in nearly every stage of the RNA life cycle, including transcription, pre-mRNA splicing, nuclear export, and translation (De Bortoli et al., 2021; Mo et al., 2021; Ullah et al., 2022; Weis and Hondele, 2022; Trussina et al., 2025).
The functional unit of DDX3X comprises the canonical D1D2 helicase core plus short N- and C-terminal extensions (NTE and CTE) required for full activity (Figure 2A). In the RNA-unbound state, structural analysis reveals that the two RecA-like domains no longer maintain a compact arrangement; instead, they attain an open V-shaped conformation, with their catalytic cores splayed apart and minimal interdomain contacts (Saito et al., 2024). Substrate binding drives a large conformational rearrangement that closes the interdomain cleft, generating a compact structure that encircles the RNA. The DDX3X D1D2 core bound to a 23-bp dsRNA (Protein Data Bank [PDB]: 6O5F), captured in an unwound state, reveals a 2:1 binding stoichiometry: two DDX molecules engage a single 2-trans A-form duplex, with each D1D2 unit primarily contacting one strand (Swarup and Bolger, 2024) (Figure 2B). The resulting D1D2:dsRNA:D1D2 assembly forms a molecular clip in which four RecA-like domains (two D1, two D2) sandwich the dsRNA. The NTE and CTE are proposed to facilitate ATP and RNA binding to DDX3X, respectively. Mechanistic studies reveal that the RNA-stimulated interaction between DDX3X and ATP requires an N-terminal ATP-binding loop (residues 152 to 160), while deletion of the RDYR motif within the CTE impairs RNA unwinding activity (Zhang et al., 2023; Tsai et al., 2024). Nuclear export signals (NES) identified in both terminal domains correlate with the tissue-specific subcellular localization of DDX3X, which localizes to either the cytoplasm or nucleus depending on cellular context (Swarup and Bolger, 2024). These findings demonstrate the functional importance of flanking regions in modulating DDX3X activity.
Figure 2
3.2 DDX21: nucleolar helicase in genome stability and R-loop resolution
DDX21 is a major nucleolar helicase whose role in genome stability has been implicated in R-loop-related stress (Chen et al., 2020; Wang et al., 2021; Chen et al., 2022; Wang et al., 2024). DDX21 depletion leads to RNaseH-dependent accumulation of DNA damage (Hao et al., 2024). Depletion of DDX21 leads to a concomitant elevation in DNA damage markers and DNA: RNA hybrid levels specifically at its chromatin-associated target genes, providing evidence that this helicase functions to prevent or dismantle R-loop structures under physiological conditions (Zhang et al., 2011; Lavergne and Roignant, 2024; Chen et al., 2026). R-loops play important physiological roles in transcription regulation, immunoglobulin class switching, and DNA replication (Lavergne and Roignant, 2024). Their unchecked accumulation can lead to replication stress, DNA damage, and genome instability (Tang et al., 2024).
DDX21 harbors signature motifs of the DExD-box family and exhibits RNA unwinding, ATPase, and G-quadruplex resolvase activities (Chen et al., 2020; Gao et al., 2023). Its helicase core adopts a canonical bilobed fold with two RecA-like domains (D1 and D2) connected by a flexible linker (Figure 3A). Crystal structures of the human DDX21 core (residues 188 to 563) have been captured in three distinct catalytic states: (i) AMPPNP-bound in complex with a 15-mer poly(U) ssRNA at 2.24 Å resolution (post-unwound/pre-hydrolysis) (Figure 3B), (ii) ADP-bound (post-hydrolysis/post-release) (Figure 3C), and (iii) apo state (no cofactor or RNA) (Figure 3D). Comparison of these structures reveals a canonical DEAD-box closure mechanism: substrate binding brings D1 and D2 into proximity, forming a composite ATPase active site and an RNA-binding cleft. ATP hydrolysis then drives the conformational cycle that underpins RNA unwinding and RNP complex disassembly (Figure 3E).
Figure 3
3.3 DHX36: G-quadruplex recognition and antiviral immunity
DHX36 is a member of the DEAH/RHA helicase family (a sister clade to DEAD-box within DExD/H-box) and binds DNA and RNA G-quadruplexes with high affinity (Jiao et al., 2025). DHX36 is a multifunctional helicase involved in G-quadruplex resolution, telomere maintenance, translation regulation, and antiviral innate immunity (Gómez-Del Arco et al., 2024; Zhang et al., 2024; Jiao et al., 2025; Sauer et al., 2019). Beyond immune sensing, DHX36 is a well-characterized RNA G-quadruplex (rG4) resolvase (Chang-Gu et al., 2021; Cheng et al., 2025). rG4s are non-canonical four-stranded nucleic acid structures found throughout the transcriptome that modulate gene expression by engaging G4-binding proteins (G4BPs) (Cheng et al., 2025; Sato et al., 2025).
DHX36 displays a modular domain organization typical of the DEAH/RHA helicase family. The N-terminal region contains a glycine-rich element and the DHX36-specific motif (DSM), which is critical for G-quadruplex recognition (Figure 4A). High-resolution structural data for full-length human DHX36 remain scarce; most available structures are of truncated constructs. The most detailed structural insights come from the co-crystal structure of bovine DHX36 bound to a DNA G-quadruplex bearing a 3′ single-stranded overhang. This structure reveals a trefoil architecture in which RecA1, RecA2, and the C-terminal domain adopt a three-lobed configuration (Figure 4B). The N-terminal extension, connected to RecA1 via a disordered linker, folds into two α-helices; the N-proximal helix harbors the DSM and extends outward from the helicase core, docking onto the 5′ (top) face of the G-quadruplex. The DSM α-helix and the OB subdomain confer selective recognition of parallel G-quadruplex topologies (Fu et al., 2024; Bartosik et al., 2025).
Figure 4
The structure of human DHX36 has not yet been experimentally determined. To address this gap, AlphaFold2 (AF2) was used to predict its structure, which was then compared with the crystal structures of bovine and mouse DHX36 (Tunyasuvunakool et al., 2021; Wayment-Steele et al., 2024). After removing the DSM region (low-confidence prediction of disordered linker regions), the RMSD between the human DHX36 AF2 model and bovine DHX36 crystal structure (PDB ID: 5VHE) was 1.876 Å; specifically, the RMSD for the amino acid 1 to 700 region was 1.509 Å, indicating that the core structural domains of the two proteins are highly conserved (Figure 4C). By contrast, the RMSD between the human DHX36 AF2 model and mouse DHX36 (PDB ID: 6UP2) was 0.514 Å, indicating higher structural similarity (Figure 4D). Multiple sequence alignment of DHX36 orthologs from human, bovine, and mouse confirms high sequence conservation across the core helicase domains, with divergence concentrated in the N-terminal glycine-rich and DSM regions (Supplementary Figure S1). These comparisons reveal that the human DHX36 model is less compact and contains more flexible regions than the bovine and mouse DHX36 crystal structures, potentially explaining the difficulty in crystallizing human DHX36.
3.4 RIG-I-like receptors: viral RNA sensing and conformational dynamics
RIG-I-like receptors, RIG-I (DDX58), MDA5, and LGP2, are cytoplasmic viral RNA sensors that trigger innate immunity and inflammation (Onomoto et al., 2021; Oshiumi et al., 2016; Ahmad et al., 2018; Thuner and Coutant, 2023; Chen et al., 2026). RIG-I and MDA5 have non-overlapping ligand specificities (Kato et al., 2021; Lang et al., 2017; Meng et al., 2017): RIG-I recognizes 5′-triphosphorylated ssRNA and blunt-ended dsRNA, whereas MDA5 detects long dsRNA duplexes independent of 5′ phosphorylation (Song et al., 2022; Pitré et al., 2025). Both receptors signal through the mitochondrial antiviral-signaling protein (MAVS), which activates IKK and TBK1 cascades to drive NF-κB activation and type I IFN production (Yin et al., 2015; Li et al., 2025; Nguyen et al., 2025; Kim et al., 2025).
RIG-I adopts a tripartite domain architecture: an N-terminal tandem caspase activation and recruitment domain (CARD) module, a central DExD/H-box helicase core, and a C-terminal regulatory domain (RD; also called repressor domain) (Figure 5A). The helicase core comprises two RecA-like domains, Hel1 and Hel2. In the autoinhibited apo state, Hel1 and Hel2 adopt an open, V-shaped arrangement; upon RNA engagement, the two domains undergo a large conformational rearrangement, closing into a compact ring that fully encircles the RNA ligand (Figure 5B). A notable structural feature is the pincer: a V-shaped element formed by two long α-helices that project from Hel2, connect to the C-terminal domain (CTD), and clasp an α-helix extending from Hel1. This pincer-CTD network creates a rigid structural framework that couples RNA binding to the allosteric activation of downstream signaling (Genoyer et al., 2025; Kirchhoff et al., 2025).
Figure 5
MDA5 shares the same domain organization as RIG-I but employs a fundamentally different activation mechanism: it assembles into helical filaments along the length of dsRNA (Kato et al., 2006; Lu et al., 2024). The E3 ubiquitin ligase TRIM65 regulates MDA5 activity through direct binding: its PRY/SPRY (PSpry) domain contacts the Hel2 subdomain of MDA5, engaging two adjacent α-helices (α1 and α3) on the outer surface of the filament (Figure 5C). Despite substantial conformational changes in the overall helicase core upon RNA and ATP binding, the Hel2 subdomain, particularly the α1/α3 region, maintains a stable conformation across monomeric and filamentous states (Dias Junior et al., 2019; Luo et al., 2026). These structural insights provide a foundation for understanding how RLR family helicases sense viral RNA and activate innate immune responses.
3.5 DEAD-box helicases in plant stress responses
While the structural paradigms above come primarily from animal systems, DEAD-box helicases are equally important in plants, where they have been implicated in development, hormone signaling, and abiotic stress responses (Linder and Owttrim, 2009; Li et al., 2023). Several plant DEAD-box helicases have been directly linked to cold or other abiotic stress tolerance. In A. thaliana, AtRH7/PRH75, a homolog of human DDX21, participates in pre-rRNA processing and is required for plant development and cold tolerance; AtRH7 mutants show retarded growth and increased sensitivity to low temperatures (Huang et al., 2016). The DEAD-box helicase DDX42 plays a critical role in pre-mRNA splicing under cold stress, and its loss leads to defective splicing of cold-responsive genes and reduced chilling tolerance (Lu et al., 2020). More recently, an RNA helicase was shown to coordinate with iron signal regulators to alleviate chilling stress in A. thaliana, linking RNA metabolism to nutrient signaling under cold conditions (Xing et al., 2025). In tomato, the DEAD-box RNA helicase SlDEAD39 has been implicated in plant development and salt response (Capel et al., 2020). These studies establish that DEAD-box helicases are integral components of the plant abiotic stress response network, and that the structural and mechanistic principles derived from animal homologs provide a valuable framework for interpreting their roles in non-model plant species such as rubber tree.
4 DDX helicases in rubber tree cold-stress response: from multi-omics data to structural prediction
As discussed in Section 1, rubber tree is a tropical crop highly susceptible to cold stress, and deciphering the molecular mechanisms underlying its cold stress response holds both fundamental and agricultural significance. Recent multi-omics investigations have revealed that RNA metabolism undergoes extensive reprogramming under cold stress conditions, with DEAD-box RNA helicases emerging as potentially important regulatory factors in this adaptive process (Mao et al., 2022; Gao et al., 2025). In this section, we summarize the identification and characterization of DDX-family proteins retrieved from rubber-tree cold-stress multi-omics datasets. We discuss their classification and putative functions derived from comparative sequence analysis and illustrate how AlphaFold2 (AF2) structural predictions can provide valuable mechanistic insights, building on the structural paradigms established in Section 3.
4.1 Identification of DDX family proteins in the rubber tree cold stress response
A previous quantitative analysis of cold-stressed rubber tree identified differentially abundant proteins in two cultivars: the cold-tolerant Yunyan77–4 and the cold-sensitive Reyan8-79 (Mao et al., 2022; Gao et al., 2025). Across ten comparison groups, nine differentially abundant DDX family proteins were identified (Table 2). RNA metabolic regulation thus operates at multiple levels, from transcription and splicing to translation and degradation, and forms an integral component of the rubber tree cold stress response network. These nine proteins fall into four functional categories: mRNA splicing/export (DDX39B isoforms), ribosome biogenesis (DDX47, DDX18, DDX21, DDX58), translation initiation (eIF4A), and RNA remodeling/quality control (DHX36, BRR2, HFM1) (Sloan and Bohnsack, 2018; Jagtap et al., 2023; Hausmann et al., 2024; Campbell et al., 2025).
Table 2
| Protein accession | Gene name | KEGG gene accession |
|---|---|---|
| A0A6A6KEA8 | DDX39B/UAP56/SUB2 | GH714_039376 |
| A0A6A6LQY2 | DDX39B/UAP56/SUB2 | GH714_023848 |
| A0A6A6M7Q9 | DDX47/RRP3 | GH714_001532 |
| A0A6A6KHX2 | DDX58 | GH714_003141 |
| A0A6A6MCP5 | SNRNP200/BRR2 | GH714_007547 |
| A0A6A6N0L7 | DDX18/HAS1 | GH714_041308 |
| A0A6A6LPP6 | DHX36/RHAU | GH714_033802 |
| A0A6A6M6P8 | HFM1/MER3 | GH714_010237 |
| A0A6A6LHZ1 | eIF4A | GH714_019340 |
Cold stress-responsive RNA helicase proteins identified in rubber-tree.
Among the nine differentially abundant DDX proteins, DDX39B/UAP56 subfamily members are the most prominently cold-responsive, with two isoforms (A0A6A6KEA8 and A0A6A6LQY2) showing differential abundance across seven and six comparison groups, respectively. DDX39B mediates mRNA export and pre-mRNA splicing in yeast and animal systems (Pérez-Calero et al., 2020; Yellamaty and Sharma, 2024; Bugai et al., 2026; Hohmann et al., 2026), suggesting that stress-induced RNA metabolic reprogramming may be conserved across eukaryotes.
4.2 Structural characterization and evolutionary conservation of HbDDX39B
Experimental structures of rubber tree DDX proteins are not yet available. However, AlphaFold2 (AF2) structure prediction offers a powerful computational alternative for inferring their structural features and functional mechanisms, the same approach used for human DHX36 in Section 3.3. HbDDX39B localizes to the cytoplasm and displays a canonical DDX39B domain architecture: two tandem RecA-like helicase domains (D1 and D2), with no additional C-terminal extensions (Liu et al., 2020).
Multiple sequence alignment (Supplementary Figure S2) shows high evolutionary conservation of HbDDX39B across divergent taxa (Gouet et al., 2003; Robert et al., 2025). HbDDX39B (A0A6A6LQY2) shares >95% identity with orthologs from Manihot esculenta (A0A2C9UAV4), Theobroma cacao (A0AB32UNN5), and Durio zibethinus (A0A6P5ZQ42). This near-identity among tropical rosid species, whose last common ancestor lived tens of millions of years ago, is consistent with purifying selection.
To formally test purifying selection, we conducted a Ka/Ks (dN/dS, ω) analysis of DDX39B coding sequences from seven species: Manihot esculenta, Hevea brasiliensis, Theobroma cacao, Durio zibethinus, Arabidopsis thaliana, Oryza sativa subsp. japonica, and Homo sapiens. Protein sequences were aligned and back-translated to codon alignments; Ka and Ks were estimated by the Nei-Gojobori method with Jukes-Cantor correction (Supplementary Figure S3; Supplementary Table S1). All 14 informative pairwise comparisons returned ω far below unity, consistent with pervasive strong purifying selection. In dicots, mean ω = 0.017, with the minimum ω = 0.011 between T. cacao and D. zibethinus (99.3% protein-sequence identity). Monocot-dicot comparisons had moderately higher ω values (mean ω = 0.037), still indicative of strong selective constraint. Ancient-divergence pairs (plant-vertebrate, Arabidopsis-rice) exhibited Ks saturation that compromises ω inference, although ~71% protein-sequence identity reveals deep conservation. No comparison gave ω > 1. DDX39B is therefore under strong purifying selection across flowering plants.
Conservation extends to temperate plants (94% identity with Arabidopsis thaliana, A0A178UKF1) and even across the plant-animal divide (73% identity with human DDX39B/UAP56) (Mungall et al., 2003), reflecting deep evolutionary conservation of this essential mRNA metabolism factor since the last eukaryotic common ancestor.
4.3 Structural basis of cold-responsive regulation: DDX39B in RNA metabolic reprogramming
AlphaFold2 structural prediction of HbDDX39B (A0A6A6LQY2) reveals a significant degree of structural conservation with its human ortholog (Figure 6, Supplementary Figure S2). The domain architecture is highly conserved between the two species (Figure 6A). Both have an N-terminal Q motif followed by two tandem RecA-like domains (D1 and D2) that form the canonical DEAD-box helicase core. The rubber tree ortholog spans 429 residues; the human ortholog, 428. Structural superposition of the AF2-predicted models shows near-perfect congruence between the two proteins (Figure 6B). The RMSD across the core helicase domain is only 0.299 Å, significantly low given that these proteins diverged over one billion years ago. Both D1 and D2 domains superimpose almost identically, as seen in the magnified views.
Figure 6
To further validate the AF2 predictions, both computational models were compared with the crystal structure of human DDX39B (PDB ID: 1XTI), an experimentally determined structure (Shi et al., 2004). All three structures superimpose well, supporting that the AF2-derived model of rubber-tree DDX39B adopts the canonical DEAD-box helicase core fold (Figure 6C). The surface electrostatic potential distributions are also similar between the human crystal structure and the rubber tree predicted model (Figure 6D, E). Both show a characteristic pattern: positively charged regions flanking the RNA-binding cleft and negatively charged patches on the opposite face. The near-identity in fold, surface charge, and domain organization across such vast evolutionary distance is consistent with strong functional constraint on DDX39B in core RNA metabolic processes. We caution, however, that these are computational structural predictions, and that higher-precision structures remain to be resolved through experimental approaches such as X-ray crystallography or cryo-EM.
The high conservation of DDX39B among tropical plants, coupled with its pronounced down-regulation under cold stress, carries important implications for understanding the molecular basis of tropical plant cold sensitivity. In contrast to temperate plants, which have evolved cold acclimation mechanisms involving C-repeat binding factor/dehydration-responsive element-binding (CBF/DREB) transcription factors and extensive transcriptomic reprogramming, tropical plants generally lack the capacity for cold acclimation and suffer severe damage even at moderately low temperatures (Taylor et al., 2019; Crous et al., 2022; Zhu et al., 2024; Liu et al., 2026). The observation that DDX39B is highly conserved in tropical plants and is strongly down-regulated by cold suggests that the cold sensitivity of tropical plants may be partially attributable to the inherent vulnerability of their RNA metabolic machinery to low temperatures. The high sequence conservation likely reflects a historical absence of selective pressure for cold-adaptive mutations in tropical environments, resulting in a DDX39B enzyme that is optimized for warm temperatures but may lose catalytic efficiency or become misregulated under cold conditions.
From a mechanistic perspective, the cold-induced down-regulation of DDX39B could impact several downstream RNA metabolic processes. As a homolog of yeast Sub2 and human UAP56, DDX39B is known to function in pre-mRNA splicing and mRNA nuclear export (Pérez-Calero et al., 2020; Hohmann et al., 2026). Under cold stress, reduced DDX39B abundance could lead to impaired splicing and nuclear export of cold-responsive transcripts, including those encoding CBF/DREB transcription factors, cold-regulated (COR) proteins, and enzymes involved in cryoprotective metabolite synthesis, thereby attenuating the cold acclimation response. Alternatively, DDX39B down-regulation may represent an adaptive energy-conservation mechanism, slowing energy-intensive RNA processing under stress conditions. Distinguishing between these possibilities will require targeted functional studies, including transcriptome-wide analysis of splicing and mRNA export changes in DDX39B-manipulated rubber tree lines under cold stress. The identification of specific RNA substrates of DDX39B in rubber tree, through techniques such as CLIP-seq or RIP-seq, would provide critical mechanistic links between cold stress, DDX39B activity, and downstream physiological responses.
5 Concluding remarks and future perspectives
This review synthesizes current structural knowledge of the DExD/H-box helicase family and integrates recent multi-omics evidence from rubber tree. It identifies DDX39B as a potentially important component of the cold-responsive RNA metabolic network, whose deep evolutionary conservation points to a fundamental role in RNA metabolic homeostasis. The integrative framework adopted here, combining multi-omics datasets with AlphaFold2 structure prediction, provides a generalizable strategy for mechanistic investigations in non-model plant species. The identification of DDX39B as a candidate cold-responsive factor in rubber tree, coupled with its high sequence conservation across tropical plant species, highlights several key priorities for future experimental work.
5.1 Structural validation and temperature-dependent enzymology
Computational structure prediction, while powerful, cannot substitute for experimentally determined structures. High-resolution crystal or cryo-EM structures of HbDDX39B in its apo state and in complex with RNA substrates and non-hydrolyzable ATP analogs would validate the AF2 model and enable precise mapping of catalytic residues and RNA-binding interfaces. Comparative structural analysis with DDX39B orthologs from cold-tolerant temperate species (e.g., Arabidopsis thaliana, Brassica rapa) may reveal subtle but functionally significant differences in domain packing, hydrogen-bond networks, or surface charge distribution that modulate helicase activity at low temperatures (Huang et al., 2016; Lu et al., 2020; Pandey et al., 2020; Li et al., 2023; Xing et al., 2025). Such comparisons could provide a structural basis for the observation that tropical plants are markedly more sensitive to chilling injury than their temperate counterparts, a phenomenon whose molecular determinants remain poorly defined (Li et al., 2024; Lai et al., 2025; Zhou et al., 2025).
5.2 Functional dissection of DDX39B in cold tolerance
A central unresolved question is whether DDX39B downregulation represents an adaptive energy-conservation mechanism or a passive consequence of cold-induced cellular damage that contributes to chilling injury. Distinguishing between these possibilities is critical for understanding the role of RNA metabolic reprogramming in the cold stress response. The AF2 structural model provides a rational framework for designing separation-of-function mutations that selectively disrupt ATPase activity, RNA binding, or protein-protein interactions, enabling precise dissection of which biochemical activities underlie the cold response phenotype. Identifying the upstream signaling pathways that modulate DDX39B expression, whether through cold-responsive transcription factors (e.g., the CBF/DREB regulon) or post-translational modifications (e.g., phosphorylation, SUMOylation), will clarify how cold signals are transduced to the RNA metabolism machinery. Transcriptome-wide splicing analysis and mRNA export assays in DDX39B-manipulated lines would further establish the mechanistic links between DDX39B activity and cold-responsive gene expression.
5.3 The A0A6A6KEA8 isoform: a putative chimeric helicase
The predicted LysM and protein kinase domains in the nuclear DDX39B isoform A0A6A6KEA8 represent a potentially novel domain architecture not previously reported in the DDX39B subfamily (Gust et al., 2012). If validated experimentally, this isoform could constitute a new class of multifunctional helicases that integrate RNA metabolic functions with stress signaling, perhaps by sensing cell wall-derived signals through the LysM domain or modulating pathway activity via kinase-mediated phosphorylation (Buendia et al., 2018; Tan et al., 2025). Systematic characterization of this isoform, including domain deletion analysis, subcellular localization studies, and interaction proteomics, promises to uncover previously unrecognized modes of helicase regulation in plants.
5.4 Translational implications for tropical crop improvement
The findings presented here have potential translational implications for rubber tree improvement and, more broadly, for tropical crop cold tolerance. Rubber cultivation is currently limited to tropical and subtropical regions where temperatures remain consistently warm; in marginal cultivation areas, such as the highlands of mainland Southeast Asia, parts of southern China (Yunnan, Guangxi), and emerging cultivation zones in West Africa, periodic cold events cause significant yield losses and restrict the geographic expansion of rubber farming. The development of cold-tolerant rubber varieties could therefore expand cultivation into marginally suitable lands, enhance production stability in existing regions, and improve the resilience of smallholder livelihoods dependent on rubber.
The >95% sequence identity of DDX39B among tropical species, including cassava (Manihot esculenta), cacao (Theobroma cacao), and jatropha (Jatropha curcas), all of which are economically important and cold-sensitive, suggests that findings from rubber trees may have broad translational relevance. If DDX39B-mediated RNA metabolic reprogramming is indeed a conserved determinant of tropical plant cold sensitivity, targeted modulation of its expression or activity could provide a general strategy for engineering chilling tolerance across multiple crop species. The HbDDX39B structural model reported here provides a foundation for structure-guided protein engineering aimed at enhancing helicase stability or catalytic efficiency at low temperatures. DDX39B itself represents a promising target for molecular breeding, either through marker-assisted selection of favorable alleles or via transgenic approaches, to develop cold-tolerant rubber tree varieties suitable for cultivation in marginally suitable regions (Wei et al., 2025). A conceptual framework linking DDX39B-mediated cold stress responses to potential agricultural applications is presented in Figure 7.
Figure 7
5.5 Methodological outlook
The integrative strategy presented here, combining quantitative multi-omics, AlphaFold2 structure prediction and cross-species comparative analysis, constitutes a generalizable conceptual framework to facilitate functional characterization of stress-responsive proteins in non-model organisms. As structural-prediction tools advance and multi-omics datasets for diverse plant species continue to expand, this computational approach holds growing potential to bridge the gap between large-scale omics discoveries and mechanistic interpretations in plant-stress biology.
Statements
Author contributions
BG: Conceptualization, Writing – review & editing, Writing – original draft, Investigation. MX: Writing – original draft. CM: Writing – original draft, Resources. JL: Supervision, Writing – review & editing, Funding acquisition.
Funding
The author(s) declared that financial support was received for this work and/or its publication. This work was supported by the Yunnan Provincial Basic Research Program (202501CF070188; 202401AS070083; 202601AS070002), Yunnan Technology Innovation Center of Natural Rubber (202605AK340010); Yunnan Key Laboratory of Sustainable Utilization Research on Rubber Tree (No. 202405AG340001); the Start-up Grant from Yunnan Institute of Tropical Crops (YITC2025-2); Yunnan Academician and Expert Workstation Project (202605AF350029), and Yunnan Special Fund for Scientific and Technological Innovation of Tropical Crops (RF2026-2).
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpls.2026.1959829/full#supplementary-material
References
1
AhmadS.MuX.YangF.GreenwaldE.ParkJ. W.JacobE.et al. (2018). Breaching self-tolerance to alu duplex rna underlies mda5-mediated inflammation. Cell.172, 797–810. doi: 10.1016/j.cell.2017.12.016
2
BaiR.WanR.WangL.XuK.ZhangQ.LeiJ.et al. (2021). Structure of the activated human minor spliceosome. Science371, eabg0879. doi: 10.1126/science.abg0879
3
BartosikA. R.HouP.TangS.VaughnJ. P.SmaldinoP. J.RatanA.et al. (2025). Loss of dhx36/g4r1, a g4 resolvase, drives genome instability and regulates innate immune gene expression in cancer cells. Nucleic Acids Res.53, gkaf621. doi: 10.1093/nar/gkaf621
4
BertramK.El AyoubiL.DybkovO.AgafonovD. E.WillC. L.HartmuthK.et al. (2020). Structural insights into the roles of metazoan-specific splicing factors in the human step 1 spliceosome. Mol. Cell80, 127–139. doi: 10.1016/j.molcel.2020.09.012
5
Brito QueridoJ.SokabeM.KraatzS.GordiyenkoY.SkehelJ. M.FraserC. S.et al. (2020). Structure of a human 48s translational initiation complex. Science369, 1220–1227. doi: 10.1126/science.aba4904
6
BuchwaldG.SchüsslerS.BasquinC.Le HirH.ContiE. (2013). Crystal structure of the human eif4aiii-cwc22 complex shows how a dead-box protein is inhibited by a mif4g domain. Proc. Natl. Acad. Sci. U.S.A.110, E4611–E4618. doi: 10.1073/pnas.1314684110
7
BuendiaL.GirardinA.WangT.CottretL.LefebvreB. (2018). Lysm receptor-like kinase and lysm receptor-like protein families: an update on phylogeny and functional characterization. Front. Plant Sci.9, 1531. doi: 10.3389/fpls.2018.01531
8
BugaiA.HohmannU.LorenzoA.GrafM.FinL.RouvièreJ. O.et al. (2026). Molecular basis of polyadenylated rna fate determination in the nucleus. Nature655, 1070–1078. doi: 10.1038/s41586-026-10650-0
9
CaiH. M.QiuY. R.TanY.CaiK.ChengS.ZhongH. J.et al. (2025). Ddx3x mutation and epstein-barr virus cooperate to induce r-loop-dependent oncogenesis. Cell Rep.44, 116237. doi: 10.1016/j.celrep.2025.116237
10
CampbellA.EsserH. F.BurroughsA. M.BerninghausenO.AravindL.BeckerT.et al. (2025). The rna helicase hrpa rescues collided ribosomes in e. coli. Mol. Cell85, 999–1007. doi: 10.1016/j.molcel.2025.01.018
11
CapelC.AlbaladejoI.EgeaI.MassarettoI. L.Yuste-LisbonaF. J.PinedaB.et al. (2020). The res (restored cell structure by salinity) tomato mutant reveals the role of the dead-box rna helicase sldead39 in plant development and salt response. Plant Cell Environ.43, 1722–1739. doi: 10.1111/pce.13776
12
Chang-GuB.BradburnD.YangyuoruP. M.RussellR. (2021). The dhx36-specific-motif (dsm) enhances specificity by accelerating recruitment of dna g-quadruplex structures. Biol. Chem.402, 593–604. doi: 10.1515/hsz-2020-0302
13
ChaoJ.WuS.ShiM.XuX.GaoQ.DuH.et al. (2023). Genomic insight into domestication of rubber tree. Nat. Commun.14, 4651. doi: 10.1038/s41467-023-40304-y
14
CharentonC.WilkinsonM. E.NagaiK. (2019). Mechanism of 5' splice site transfer for human spliceosome activation. Science364, 362–367. doi: 10.1126/science.aax3289
15
ChenY.GeQ.GaoY.ZhangX.XuL.LiQ.et al. (2026). Interactome profiling reveals the lcmv nucleoprotein co-opts ddx helicases through conserved interfaces. Int. J. Biol. Macromol.337, 149434. doi: 10.1016/j.ijbiomac.2025.149434
16
ChenZ.HuangJ.LiJ. (2022). Protein purification, crystallization, and structure determination of human dead-box rna helicase ddx21 in different unwinding states. STAR Protoc.3, 101642. doi: 10.1016/j.xpro.2022.101642
17
ChenM.JiangK.ZhangQ.XiaoX.ZhuL.SangY.et al. (2026). Ddx21 links braf(v600e) and tert to promote thyroid cancer progression. Thyroid36, 305–319. doi: 10.1177/10507256261417697
18
ChenZ.LiZ.HuX.XieF.KuangS.ZhanB.et al. (2020). Structural basis of human helicase ddx21 in rna binding, unwinding, and antiviral signal activation. Adv. Sci.7, 2000532. doi: 10.1002/advs.202000532
19
ChengJ.BerninghausenO.BeckmannR. (2021). A distinct assembly pathway of the human 39s late pre-mitoribosome. Nat. Commun.12, 4544. doi: 10.1038/s41467-021-24818-x
20
ChengL. Y.RipinN.CechT. R.ParkerR. (2025). Dhx36 modulates stress granule assembly independent of recruitment of mrnas with g-quadruplex sequence motifs. Nucleic Acids Res.53, gkaf938. doi: 10.1093/nar/gkaf938
21
CordinO.BanroquesJ.TannerN. K.LinderP. (2006). The dead-box protein family of rna helicases. Gene367, 17–37. doi: 10.1016/j.gene.2005.10.019
22
CrousK. Y.UddlingJ.De KauweM. G. (2022). Temperature responses of photosynthesis and respiration in evergreen trees from boreal to tropical latitudes. New Phytol.234, 353–374. doi: 10.1111/nph.17951
23
De BortoliF.EspinosaS.ZhaoR. (2021). Deah-box rna helicases in pre-mrna splicing. Trends Biochem. Sci.46, 225–238. doi: 10.1016/j.tibs.2020.10.006
24
Devasahayam Arokia BalayaR.KanekarS.KumarS.KandasamyR. K. (2025). Role of dead/deah-box helicases in immunity, infection and cancers. Cell Commun. Signaling23, 292. doi: 10.1186/s12964-025-02225-9
25
Dias JuniorA. G.SampaioN. G.RehwinkelJ. (2019). A balancing act: mda5 in antiviral immunity and autoinflammation. Trends Microbiol.27, 75–85. doi: 10.1016/j.tim.2018.08.007
26
DuttaS.GuptaG.ChoiY. W.KotakaM.FieldingB. C.SongJ.et al. (2012). The variable n-terminal region of ddx5 contains structural elements and auto-inhibits its interaction with ns5b of hepatitis c virus. Biochem. J.446, 37–46. doi: 10.1042/BJ20120001
27
Fairman-WilliamsM. E.GuentherU.JankowskyE. (2010). Sf1 and sf2 helicases: family matters. Curr. Opin. Struct. Biol.20, 313–324. doi: 10.1016/j.sbi.2010.03.011
28
FuL.WuQ.FuJ. (2024). Exploring the biological roles of dhx36, a dna/rna g-quadruplex helicase, highlights functions in male infertility: a comprehensive review. Int. J. Biol. Macromol.268, 131811. doi: 10.1016/j.ijbiomac.2024.131811
29
FuQ.YuanY. A. (2013). Structural insights into risc assembly facilitated by dsrna-binding domains of human rna helicase a (dhx9). Nucleic Acids Res.41, 3457–3470. doi: 10.1093/nar/gkt042
30
GadekM.SherrE. H.FloorS. N. (2023). The variant landscape and function of ddx3x in cancer and neurodevelopmental disorders. Trends Mol. Med.29, 726–739. doi: 10.1016/j.molmed.2023.06.003
31
GaoB.LiX.LiS.WangS.WuJ.LiJ. (2022). Pan-cancer analysis identifies rna helicase ddx1 as a prognostic marker. Phenomics2, 33–49. doi: 10.1007/s43657-021-00034-x
32
GaoC.MaoC.LiuZ.ZhengC.LiuN.LiC.et al. (2025). Transcriptomic response analysis of rubber tree saplings to water-deficit stress at single-cell resolution. Commun. Biol.8, 1513. doi: 10.1038/s42003-025-09046-z
33
GaoH.WeiH.YangY.LiH.LiangJ.YeJ.et al. (2023). Phase separation of ddx21 promotes colorectal cancer metastasis via mcm5-dependent emt pathway. Oncogene42, 1704–1715. doi: 10.1038/s41388-023-02687-6
34
GenoyerE.WilsonJ.AmesJ. M.StokesC.MorenoD.EtzyonN.et al. (2025). Exposure of negative-sense viral rna in the cytoplasm initiates innate immunity to west nile virus. Mol. Cell85, 1147–1161. doi: 10.1016/j.molcel.2025.01.015
35
Gómez-Del ArcoP.IsernJ.Jimenez-CarreteroD.López-MaderueloD.Piñeiro-SabarísR.El Abdellaoui-SoussiF.et al. (2024). The g4 resolvase dhx36 modulates cardiomyocyte differentiation and ventricular conduction system development. Nat. Commun.15, 8602. doi: 10.1038/s41467-024-52809-1
36
GouetP.RobertX.CourcelleE. (2003). Espript/endscript: extracting and rendering sequence and 3d information from atomic structures of proteins. Nucleic Acids Res.31, 3320–3323. doi: 10.1093/nar/gkg556
37
GustA. A.WillmannR.DesakiY.GrabherrH. M.NürnbergerT. (2012). Plant lysm proteins: modules mediating symbiosis and immunity. Trends Plant Sci.17, 495–503. doi: 10.1016/j.tplants.2012.04.003
38
HaoJ. D.LiuQ. L.LiuM. X.YangX.WangL. M.SuS. Y.et al. (2024). Ddx21 mediates co-transcriptional rna m(6)a modification to promote transcription termination and genome stability. Mol. Cell84, 1711–1726. doi: 10.1016/j.molcel.2024.03.006
39
HausmannS.GeiserJ.AllenG. E.GeslainS. A. M.ValentiniM. (2024). Intrinsically disordered regions regulate rhle rna helicase functions in bacteria. Nucleic Acids Res.52, 7809–7824. doi: 10.1093/nar/gkae511
40
HeB.CaiQ.QiaoL.HuangC. Y.WangS.MiaoW.et al. (2021). Rna-binding proteins contribute to small rna loading in plant extracellular vesicles. Nat. Plants7, 342–352. doi: 10.1038/s41477-021-00863-8
41
HeS.LiB.ChenF.HuangJ.DongY.LiuS.et al. (2026). Ddx24 modulates angiogenesis by promoting ccr4-not complex-dependent mrna decay. Nucleic Acids Res.54, gkag130. doi: 10.1093/nar/gkag130
42
HeddiB.CheongV. V.MartadinataH.PhanA. T. (2015). Insights into g-quadruplex specific recognition by the deah-box helicase rhau: solution structure of a peptide-quadruplex complex. Proc. Natl. Acad. Sci. U.S.A.112, 9608–9613. doi: 10.1073/pnas.1422605112
43
HeddiB.CheongV. V.SchmittE.MechulamY.PhanA. T. (2020). Recognition of different base tetrads by rhau (dhx36): x-ray crystal structure of the g4 recognition motif bound to the 3'-end tetrad of a dna g-quadruplex. J. Struct. Biol.209, 107399. doi: 10.1016/j.jsb.2019.10.001
44
Hernández-ReyesY.Fonseca-RodríguezC.FreireR.SmitsV. A. J. (2025). Ddx37 and ddx50 maintain genome stability by preventing transcription-dependent r-loop formation. J. Mol. Biol.437, 169061. doi: 10.1016/j.jmb.2025.169061
45
HiaF.WuY.YoshinagaM.Goto-ItoS.IwasakiW.ImamiK.et al. (2026). Human dhx29 detects nonoptimal codon usage to regulate mrna stability. Science392, eadw288. doi: 10.1126/science.adw0288
46
HohmannU.GrafM.TiriánL.Pacheco-FiallosB.SchellhaasU.FinL.et al. (2026). An atp-gated molecular switch orchestrates human mrna export. Nature649, 1042–1050. doi: 10.1038/s41586-025-09832-z
47
HongS. K.KimK.SongE. J.KimE. E. (2016). Structural basis for the interaction between the ius-spry domain of ranbpm and ddx-4 in germ cell development. J. Mol. Biol.428, 4330–4344. doi: 10.1016/j.jmb.2016.09.004
48
HuangC. K.ShenY. L.HuangL. F.WuS. J.YehC. H.LuC. A. (2016). The dead-box rna helicase atrh7/prh75 participates in pre-rrna processing, plant development and cold tolerance in arabidopsis. Plant Cell Physiol.57, 174–191. doi: 10.1093/pcp/pcv188
49
JagtapP. K. A.MüllerM.KissA. E.ThomaeA. W.LapougeK.BeckM.et al. (2023). Structural basis of rna-induced autoregulation of the dexh-type rna helicase maleless. Mol. Cell83, 4318–4333. doi: 10.1016/j.molcel.2023.10.026
50
JiaY.ChengZ.BharathS. R.SunQ.SuN.HuangJ.et al. (2021). Crystal structure of the ints3/ints6 complex reveals the functional importance of ints3 dimerization in dsb repair. Cell Discov.7, 66. doi: 10.1038/s41421-021-00283-0
51
JiaZ.RuiP.FangX.HanK.YuT.LuY.et al. (2025). Proteolysis of host dead-box rna helicase by potyviral proteases activates plant immunity. New Phytol.245, 1655–1672. doi: 10.1111/nph.20318
52
JiangY.ZhuY.QiuW.LiuY. J.ChengG.LiuZ. J.et al. (2017). Structural and functional analyzes of human ddx41 dead domain. Protein Cell. 8, 72–76. doi: 10.1007/s13238-016-0351-9
53
JiaoY. X.BuG. W.WuY. W.WuY. K.ChenB. B.SheM. T.et al. (2025). Dhx36-mediated g-quadruplexes unwinding is essential for oocyte and early embryo development in mice. Sci. Bull.70, 1295–1310. doi: 10.1016/j.scib.2025.02.017
54
KatoK.AhmadS.ZhuZ.YoungJ. M.MuX.ParkS.et al. (2021). Structural analysis of rig-i-like receptors reveals ancient rules of engagement between diverse rna helicases and trim ubiquitin ligases. Mol. Cell81, 599–613. doi: 10.1016/j.molcel.2020.11.047
55
KatoH.TakeuchiO.SatoS.YoneyamaM.YamamotoM.MatsuiK.et al. (2006). Differential roles of mda5 and rig-i helicases in the recognition of rna viruses. Nature441, 101–105. doi: 10.1038/nature04734
56
KellnerJ. N.MeinhartA. (2015). Structure of the spry domain of the human rna helicase ddx1, a putative interaction platform within a dead-box protein. Acta Crystallographica Section F71, 1176–1188. doi: 10.1107/S2053230X15013709
57
KimM.PyoY.HyunS. I.JeongM.ChoiY.KimV. N. (2025). Exogenous rna surveillance by proton-sensing trim25. Science388, eads4539. doi: 10.1126/science.ads4539
58
KirchhoffA.HerznerA. M.UrbanC.PirasA.DüsterR.MahlbergJ.et al. (2025). Rna-binding proteins hnrnpm and elavl1 promote type-i interferon induction downstream of the nucleic acid sensors cgas and rig-i. EMBO J.44, 824–853. doi: 10.1038/s44318-024-00331-x
59
KögelA.KeidelA.BonneauF.SchäferI. B.ContiE. (2022). The human ski complex regulates channeling of ribosome-bound rna to the exosome via an intrinsic gatekeeping mechanism. Mol. Cell82, 756–769. doi: 10.1016/j.molcel.2022.01.009
60
LaiX.YanJ.ChenZ.ZhangY.LuoF.CaiG.et al. (2025). Dynamic changes in the transcriptome of tropical region-originated king grasses in response to cold stress. Front. Plant Sci.16, 1511466. doi: 10.3389/fpls.2025.1511466
61
LangX.TangT.JinT.DingC.ZhouR.JiangW. (2017). Trim65-catalized ubiquitination is essential for mda5-mediated antiviral innate immunity. J. Exp. Med.214, 459–473. doi: 10.1084/jem.20160592
62
LavergneG.RoignantJ. (2024). Ddx21: the link between m(6)a and r-loops. Mol. Cell84, 1631–1632. doi: 10.1016/j.molcel.2024.04.005
63
LiX.LiC.ZhuJ.ZhongS.ZhuH.ZhangX. (2023). Functions and mechanisms of rna helicases in plants. J. Exp. Bot.74, 2295–2310. doi: 10.1093/jxb/erac462
64
LiR.SongY.WangX.ZhengC.LiuB.ZhangH.et al. (2024). Osnac5 orchestrates osabi5 to fine-tune cold tolerance in rice. J. Integr. Plant Biol.66, 660–682. doi: 10.1111/jipb.13585
65
LiY.WuS.TianX.KongC.HongW.XiaoT.et al. (2025). The structural basis of trim25-mediated regulation of rig-i. J. Biol. Chem.301, 108367. doi: 10.1016/j.jbc.2025.108367
66
LiaoX.ZhangS.LiX.QianW.LiM.ChenS.et al. (2024). Dynamic structural remodeling of linc01956 enhances temozolomide resistance in mgmt-methylated glioblastoma. Sci. Transl. Med.16, eado1573. doi: 10.1126/scitranslmed.ado1573
67
LinD. H.CorreiaA. R.CaiS. W.HuberF. M.JetteC. A.HoelzA. (2018). Structural and functional analysis of mrna export regulation by the nuclear pore complex. Nat. Commun.9, 2319. doi: 10.1038/s41467-018-04459-3
68
LinderP.OwttrimG. W. (2009). Plant rna helicases: linking aberrant and silencing rna. Trends Plant Sci.14, 344–352. doi: 10.1016/j.tplants.2009.03.007
69
LiuJ.ShiC.ShiC. C.LiW.ZhangQ. J.ZhangY.et al. (2020). The chromosome-based rubber tree genome provides new insights into spurge genome evolution and rubber biosynthesis. Mol. Plant13, 336–350. doi: 10.1016/j.molp.2019.10.017
70
LiuG.WangH.TangY.GaoH.WangY.SunY.et al. (2026). Research progress on cold tolerance key genes and mechanisms in four major northern China crops. Front. Plant Sci.17, 1823380. doi: 10.3389/fpls.2026.1823380
71
LohP. G.YangH. S.WalshM. A.WangQ.WangX.ChengZ.et al. (2009). Structural basis for translational inhibition by the tumour suppressor pdcd4. EMBO J.28, 274–285. doi: 10.1038/emboj.2008.278
72
LuC. A.HuangC. K.HuangW. S.HuangT. S.LiuH. Y.ChenY. F. (2020). Dead-box rna helicase 42 plays a critical role in pre-mrna splicing under cold stress. Plant Physiol.182, 255–271. doi: 10.1104/pp.19.00832
73
LuX.PengQ.WangG. (2024). Anti-mda5 antibody-positive dermatomyositis: pathogenesis and clinical progress. Nat. Rev. Rheumatol.20, 48–62. doi: 10.1038/s41584-023-01054-9
74
LuoD.DingS. C.VelaA.KohlwayA.LindenbachB. D.PyleA. M. (2011). Structural insights into rna recognition by rig-i. Cell.147, 409–422. doi: 10.1016/j.cell.2011.09.023
75
LuoL.WangY.FangG.ChangJ.DaiX.GuH.et al. (2026). Mda5 regulates bcr signaling and b-cell function via nf-κb-mediated dnm1. Cell. Mol. Immunol.23, 168–185. doi: 10.1038/s41423-025-01352-0
76
MaS.MaoQ.WengS.TengM.LuoJ.ZhangK. (2025). Ddx3x and virus interactions: functional diversity and antiviral strategies. Front. Microbiol.16, 1630068. doi: 10.3389/fmicb.2025.1630068
77
MaoC.LiL.YangT.GuiM.LiX.ZhangF.et al. (2022). Transcriptomics integrated with widely targeted metabolomics reveals the cold resistance mechanism in hevea brasiliensis. Front. Plant Sci.13, 1092411. doi: 10.3389/fpls.2022.1092411
78
MengJ.YaoZ.HeY.ZhangR.ZhangY.YaoX.et al. (2017). Arrdc4 regulates enterovirus 71-induced innate immune response by promoting k63 polyubiquitination of mda5 through trim65. Cell Death Dis.8, e2866. doi: 10.1038/cddis.2017.257
79
MoJ.LiangH.SuC.LiP.ChenJ.ZhangB. (2021). Ddx3x: structure, physiologic functions and cancer. Mol. Cancer20, 38. doi: 10.1186/s12943-021-01325-7
80
MöhlmannS.MathewR.NeumannP.SchmittA.LührmannR.FicnerR. (2014). Structural and functional analysis of the human spliceosomal dead-box helicase prp28. Acta Crystallographica Section D.70, 1622–1630. doi: 10.1107/S1399004714006439
81
MungallA. J.PalmerS. A.SimsS. K.EdwardsC. A.AshurstJ. L.WilmingL.et al. (2003). The dna sequence and analysis of human chromosome 6. Nature425, 805–811. doi: 10.1038/nature02055
82
MurakamiK.NakanoK.ShimizuT.OhtoU. (2017). The crystal structure of human deah-box rna helicase 15 reveals a domain organization of the mammalian deah/rha family. Acta Crystallographica Section F73, 347–355. doi: 10.1107/S2053230X17007336
83
NapetschnigJ.KassubeS. A.DeblerE. W.WongR. W.BlobelG.HoelzA. (2009). Structural and functional analysis of the interaction between the nucleoporin nup214 and the dead-box helicase ddx19. Proc. Natl. Acad. Sci. U.S.A.106, 3089–3094. doi: 10.1073/pnas.0813267106
84
NgoT. D.PartinA. C.NamY. (2019). Rna specificity and autoregulation of ddx17, a modulator of microrna biogenesis. Cell Rep.29, 4024–4035. doi: 10.1016/j.celrep.2019.11.059
85
NguyenT. T. T.DangX. T. T.PhungC. D.TranL. T. N.DoN. T. P.YeoE. Y. M.et al. (2025). Safety and efficacy of kras antisense oligonucleotides and rig-i agonists delivered by extracellular vesicles for pancreatic cancer peritoneal metastasis treatment. J. Controlled Release387, 114239. doi: 10.1016/j.jconrel.2025.114239
86
NiuY.GaoC.LiuJ. (2024). Mitochondrial genome variation and intergenomic sequence transfers in hevea species. Front. Plant Sci.15, 1234643. doi: 10.3389/fpls.2024.1234643
87
OhnishiS.PääkkönenK.KoshibaS.TochioN.SatoM.KobayashiN.et al. (2009). Solution structure of the guct domain from human rna helicase ii/gu beta reveals the rrm fold, but implausible rna interactions. Proteins74, 133–144. doi: 10.1002/prot.22138
88
OnomotoK.OnoguchiK.YoneyamaM. (2021). Regulation of rig-i-like receptor-mediated signaling: interaction between host and viral factors. Cell. Mol. Immunol.18, 539–555. doi: 10.1038/s41423-020-00602-7
89
OshiumiH.KouwakiT.SeyaT. (2016). Accessory factors of cytoplasmic viral rna sensors required for antiviral innate immune response. Front. Immunol.7, 200. doi: 10.3389/fimmu.2016.00200
90
OzgurS.BasquinJ.KamenskaA.FilipowiczW.StandartN.ContiE. (2015). Structure of a human 4e-t/ddx6/cnot1 complex reveals the different interplay of ddx6-binding proteins with the ccr4-not complex. Cell Rep.13, 703–711. doi: 10.1016/j.celrep.2015.09.033
91
PandeyS.PrasadA.SharmaN.PrasadM. (2020). Linking the plant stress responses with rna helicases. Plant Sci.299, 110607. doi: 10.1016/j.plantsci.2020.110607
92
ParsyanA.SvitkinY.ShahbazianD.GkogkasC.LaskoP.MerrickW. C.et al. (2011). Mrna helicases: the tacticians of translational control. Nat. Rev. Mol. Cell Biol.12, 235–245. doi: 10.1038/nrm3083
93
Pérez-CaleroC.Bayona-FeliuA.XueX.BarrosoS. I.MuñozS.González-BasalloteV. M.et al. (2020). Uap56/ddx39b is a major cotranscriptional rna-dna helicase that unwinds harmful r loops genome-wide. Genes Dev.34, 898–912. doi: 10.1101/gad.336024.119
94
PeterD.RuscicaV.BawankarP.WeberR.HelmsS.ValkovE.et al. (2019). Molecular basis for gigyf-me31b complex assembly in 4ehp-mediated translational repression. Genes Dev.33, 1355–1360. doi: 10.1101/gad.329219.119
95
PitréE.BishtK.RemickK. A.GhorbaniA.YewdellJ. W.ElshinaE.et al. (2025). A two-step mechanism for rig-i activation by influenza virus mvrnas. Sci. Adv.11, eadw8034. doi: 10.1126/sciadv.adw8034
96
PühringerT.HohmannU.FinL.Pacheco-FiallosB.SchellhaasU.BrenneckeJ.et al. (2020). Structure of the human core transcription-export complex reveals a hub for multivalent interactions. eLife9, e61503. doi: 10.7554/eLife.61503
97
RobertX.GuillonC.GouetP. (2025). Foldscript: a web server for the efficient analysis of ai-generated 3d protein models. Nucleic Acids Res.53, W277–W282. doi: 10.1093/nar/gkaf326
98
SaitoH.HandaY.ChenM.Schneider-PoetschT.ShichinoY.TakahashiM.et al. (2024). Dmda-pata mediates rna sequence-selective translation repression by anchoring eif4a and ddx3 to gng motifs. Nat. Commun.15, 7418. doi: 10.1038/s41467-024-51635-9
99
SatoK.LyuJ.van den BergJ.BraatD.CruzV. M.Navarro LuzónC.et al. (2025). Rna transcripts regulate g-quadruplex landscapes through g-loop formation. Science388, 1225–1231. doi: 10.1126/science.adr0493
100
SauerM.JuranekS. A.MarksJ.De MagisA.KazemierH. G.HilbigD.et al. (2019). Dhx36 prevents the accumulation of translationally inactive mrnas with g4-structures in untranslated regions. Nat. Commun.10, 2421. doi: 10.1038/s41467-019-10432-5
101
SchützP.WahlbergE.KarlbergT.HammarströmM.CollinsR.FloresA.et al. (2010). Crystal structure of human rna helicase a (dhx9): structural basis for unselective nucleotide base binding in a dead-box variant protein. J. Mol. Biol.400, 768–782. doi: 10.1016/j.jmb.2010.05.046
102
ShiH.CordinO.MinderC. M.LinderP.XuR. (2004). Crystal structure of the human atp-dependent splicing and export factor uap56. Proc. Natl. Acad. Sci. U.S.A.101, 17628–17633. doi: 10.1073/pnas.0408172101
103
SinghS.Vanden BroeckA.MillerL.Chaker-MargotM.KlingeS. (2021). Nucleolar maturation of the human small subunit processome. Science373, eabj5338. doi: 10.1126/science.abj5338
104
SloanK. E.BohnsackM. T. (2018). Unravelling the mechanisms of rna helicase regulation. Trends Biochem. Sci.43, 237–250. doi: 10.1016/j.tibs.2018.02.001
105
SongH.JiX. (2019). The mechanism of rna duplex recognition and unwinding by dead-box helicase ddx3x. Nat. Commun.10, 3085. doi: 10.1038/s41467-019-11083-2
106
SongJ.ZhaoW.ZhangX.TianW.ZhaoX.MaL.et al. (2022). Mutant rig-i enhances cancer-related inflammation through activation of circrig-i signaling. Nat. Commun.13, 7096. doi: 10.1038/s41467-022-34885-3
107
StuderM. K.IvanovićL.WeberM. E.MartiS.JonasS. (2020). Structural basis for deah-helicase activation by g-patch proteins. Proc. Natl. Acad. Sci. U.S.A.117, 7159–7170. doi: 10.1073/pnas.1913880117
108
SuC.TangY.ZhengC. (2021). Dexd/h-box helicases: multifunctional regulators in antiviral innate immunity. Cell. Mol. Life Sci.79, 2. doi: 10.1007/s00018-021-04072-6
109
SullivanM. J. P.LewisS. L.Affum-BaffoeK.CastilhoC.CostaF.SanchezA. C.et al. (2020). Long-term thermal sensitivity of earth's tropical forests. Science368, 869–874. doi: 10.1126/science.aaw7578
110
SwarupA.BolgerT. A. (2024). The role of the rna helicase ddx3x in medulloblastoma progression. Biomolecules14, 803. doi: 10.3390/biom14070803
111
TanX.WangD.ZhangX.ZhengS.JiaX.LiuH.et al. (2025). A pair of lysm receptors mediates symbiosis and immunity discrimination in marchantia. Cell.188, 1330–1348. doi: 10.1016/j.cell.2024.12.024
112
TangC.YangM.FangY.LuoY.GaoS.XiaoX.et al. (2016). The rubber tree genome reveals new insights into rubber production and species adaptation. Nat. Plants2, 16073. doi: 10.1038/nplants.2016.73
113
TangW.YangY.FuZ.XuW.OuW.LiuF.et al. (2024). The rna helicase ddx21 activates yap to promote tumorigenesis and is transcriptionally upregulated by β-catenin in colorectal cancer. Oncogene43, 3227–3239. doi: 10.1038/s41388-024-03160-8
114
TaylorT. C.SmithM. N.SlotM.FeeleyK. J. (2019). The capacity to emit isoprene differentiates the photosynthetic temperature responses of tropical plant species. Plant Cell Environ.42, 2448–2457. doi: 10.1111/pce.13564
115
ThunerJ.CoutantF. (2023). Ifn-γ: an overlooked cytokine in dermatomyositis with anti-mda5 antibodies. Autoimmun. Rev.22, 103420. doi: 10.1016/j.autrev.2023.103420
116
TrussinaI. R. E. A.HartmannA.Desroches AltamiranoC.NatarajanJ.FischerC. M.AleksejczukM.et al. (2025). G3bp-driven rnp granules promote inhibitory rna-rna interactions resolved by ddx3x to regulate mrna translatability. Mol. Cell85, 585–601. doi: 10.1016/j.molcel.2024.11.039
117
TsaiS. Y.LinC. H.JiangY. T.HuangG. J.PiH.HungH. Y.et al. (2024). Ddx3 is critical for female fertility via translational control in oogenesis. Cell Death Discov.10, 472. doi: 10.1038/s41420-024-02242-6
118
TunyasuvunakoolK.AdlerJ.WuZ.GreenT.ZielinskiM.ŽídekA.et al. (2021). Highly accurate protein structure prediction for the human proteome. Nature596, 590–596. doi: 10.1038/s41586-021-03828-1
119
UllahR.LiJ.FangP.XiaoS.FangL. (2022). Dead/h-box helicases: anti-viral and pro-viral roles during infections. Virus Res.309, 198658. doi: 10.1016/j.virusres.2021.198658
120
WangL.LyuY.LiY.LiK.WenH.FengC.et al. (2021). Asxl1 promotes adrenocortical carcinoma and is associated with chemoresistance to edp regimen. Aging13, 22286–22297. doi: 10.18632/aging.203534
121
WangP.LiC.WangD.WuQ.ZengZ.GuoH.et al. (2026). Adaptive responses of tropical crops: a multi-scale omics integrated perspective. Adv. Sci.13, e76735. doi: 10.1002/advs.76735
122
WangS.YangR.SongM.LiJ.ZhouY.DaiC.et al. (2024). Current understanding of the role of ddx21 in orchestrating gene expression in health and diseases. Life Sci.349, 122716. doi: 10.1016/j.lfs.2024.122716
123
WangY.YangQ.LinF.SongX.YangG.WenD.et al. (2025). Rna binding protein ddx3x drives pancreatic cancer progression via the tle2-myl9 axis. Sci. Adv.11, eadw9519. doi: 10.1126/sciadv.adw9519
124
Wayment-SteeleH. K.OjoawoA.OttenR.ApitzJ. M.PitsawongW.HömbergerM.et al. (2024). Predicting multiple conformations via sequence clustering and alphafold2. Nature625, 832–839. doi: 10.1038/s41586-023-06832-9
125
WeiT.LiJ.LeiX.LinR.WuQ.ZhangZ.et al. (2025). Multimodal crispr screens uncover ddx39b as a global repressor of a-to-i rna editing. Cell Rep.44, 116009. doi: 10.1016/j.celrep.2025.116009
126
WeisK.HondeleM. (2022). The role of dead-box atpases in gene expression and the regulation of rna-protein condensates. Annu. Rev. Biochem.91, 197–219. doi: 10.1146/annurev-biochem-032620-105429
127
WuB.PeisleyA.TetraultD.LiZ.EgelmanE. H.MagorK. E.et al. (2014). Molecular imprinting as a signal-activation mechanism of the viral rna sensor rig-i. Mol. Cell55, 511–523. doi: 10.1016/j.molcel.2014.06.010
128
XingY.LiY.GuiX.ZhangX.HuQ.ZhaoQ.et al. (2025). An rna helicase coordinates with iron signal regulators to alleviate chilling stress in arabidopsis. Nat. Commun.16, 3988. doi: 10.1038/s41467-025-59334-9
129
YangF.BianT.ZhanX.ChenZ.XingZ.LarsenN. A.et al. (2023). Mechanisms of the rna helicases ddx42 and ddx46 in human u2 snrnp assembly. Nat. Commun.14, 897. doi: 10.1038/s41467-023-36489-x
130
YellamatyR.SharmaS. (2024). Critical cellular functions and mechanisms of action of the rna helicase uap56. J. Mol. Biol.436, 168604. doi: 10.1016/j.jmb.2024.168604
131
YinQ.FuT.LiJ.WuH. (2015). Structural biology of innate immunity. Annu. Rev. Immunol.33, 393–416. doi: 10.1146/annurev-immunol-032414-112258
132
YouS.XuJ.YinZ.WuB.WangP.HaoM.et al. (2023). Down-regulation of wwp2 aggravates type 2 diabetes mellitus-induced vascular endothelial injury through modulating ubiquitination and degradation of ddx3x. Cardiovasc. Diabetol.22, 107. doi: 10.1186/s12933-023-01818-3
133
ZhangH.Mañán-MejíasP. M.MilesH. N.PutnamA. A.MacGillivrayL. R.RickeW. A. (2024). Ddx3x and stress granules: emerging players in cancer and drug resistance. Cancers16. doi: 10.3390/cancers16061131
134
ZhangW.CaoL.YangJ.ZhangS.ZhaoJ.ShiZ.et al. (2023). Aep-cleaved ddx3x induces alternative rna splicing events to mediate cancer cell adaptation in harsh microenvironments. J. Clin. Invest.134, e173299. doi: 10.1172/JCI173299
135
ZhangX.ZhanX.YanC.ZhangW.LiuD.LeiJ.et al. (2019). Structures of the human spliceosomes before and after release of the ligated exon. Cell Res.29, 274–285. doi: 10.1038/s41422-019-0143-x
136
ZhangY.ZhaoJ.ChenX.QiaoY.KangJ.GuoX.et al. (2024). Dhx36 binding induces rna structurome remodeling and regulates rna abundance via m(6)a reader ythdf1. Nat. Commun.15, 9890. doi: 10.1038/s41467-024-54000-y
137
ZhangZ.KimT.BaoM.FacchinettiV.JungS. Y.GhaffariA. A.et al. (2011). Ddx1, ddx21, and dhx36 helicases form a complex with the adaptor molecule trif to sense dsrna in dendritic cells. Immunity34, 866–878. doi: 10.1016/j.immuni.2011.03.027
138
ZhangZ.WillC. L.BertramK.DybkovO.HartmuthK.AgafonovD. E.et al. (2020). Molecular architecture of the human 17s u2 snrnp. Nature583, 310–313. doi: 10.1038/s41586-020-2344-3
139
ZhengH.QiY.HuS.CaoX.XuC.YinZ.et al. (2020). Identification of integrator-pp2a complex (intac), an rna polymerase ii phosphatase. Science370, eabb5872. doi: 10.1126/science.abb5872
140
ZhouL.UllahF.ZouJ.ZengX. (2025). Molecular and physiological responses of plants that enhance cold tolerance. Int. J. Mol. Sci.26, 1157. doi: 10.3390/ijms26031157
141
ZhuL.ScafaroA. P.VierlingE.BallM. C.PoschB. C.StockF.et al. (2024). Heat tolerance of a tropical-subtropical rainforest tree species polyscias elegans: time-dependent dynamic responses of physiological thermostability and biochemistry. New Phytol.241, 715–731. doi: 10.1111/nph.19356
Summary
Keywords
AlphaFold2, cold stress, DExD/H-box family, RNA helicases, rubber tree, structural biology
Citation
Gao B, Xiao M, Mao C and Liu J (2026) Structural and functional perspectives on DEAD-box RNA helicases in the rubber tree cold stress response. Front. Plant Sci. 17:1959829. doi: 10.3389/fpls.2026.1959829
Received
06 August 2026
Revised
27 August 2026
Accepted
04 September 2026
Published
15 September 2026
Volume
17 - 2026
Edited by
Weimin Li, Shanghai University, China
Reviewed by
Aldrin Y. Cantila, UWA Institute of Agriculture & School of Agriculture and Environment, Australia
Iqball Faheem, The State University of New Jersey, United States
Updates
Copyright
© 2026 Gao, Xiao, Mao and Liu.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Changli Mao, maokangwan@163.com; Jin Liu, liujin06@126.com
†These authors have contributed equally to this work
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.