Emerging Roles of Non-proteolytic Ubiquitination in Tumorigenesis

Abstract

Ubiquitination is a critical type of protein post-translational modification playing an essential role in many cellular processes. To date, more than eight types of ubiquitination exist, all of which are involved in distinct cellular processes based on their structural differences. Studies have indicated that activation of the ubiquitination pathway is tightly connected with inflammation-related diseases as well as cancer, especially in the non-proteolytic canonical pathway, highlighting the vital roles of ubiquitination in metabolic programming. Studies relating degradable ubiquitination through lys48 or lys11-linked pathways to cellular signaling have been well-characterized. However, emerging evidence shows that non-degradable ubiquitination (linked to lys6, lys27, lys29, lys33, lys63, and Met1) remains to be defined. In this review, we summarize the non-proteolytic ubiquitination involved in tumorigenesis and related signaling pathways, with the aim of providing a reference for future exploration of ubiquitination and the potential targets for cancer therapies.

1 Introduction

1.1 The Ubiquitin-Proteasome System

Ubiquitination, also known as ubiquitylation, refers to the process by which ubiquitin (Ub, a small and highly conserved protein), with the help of a series of special enzymes, classifies proteins in cells, selects target proteins, and modifies those proteins (McDowell and Philpott, 2016; Seeler and Dejean, 2017; Rape, 2018). Ubiquitination plays fundamental roles in many cellular events such as cell proliferation (Kwon and Ciechanover, 2017; Werner et al., 2017; Senft et al., 2018; Song and Luo, 2019), cell cycle (Teixeira and Reed, 2013; Darling et al., 2017; Gilberto and Peter, 2017), DNA repair (Alpi and Patel, 2009; Abbas and Dutta, 2011), immune response (Heaton et al., 2016; Rudnicka and Yamauchi, 2016; Manthiram et al., 2017), transcription (Zhou et al., 2018; Imam et al., 2019; Sun et al., 2019), angiogenesis (Zhang et al., 2022), metastasis (Rossi and Rossi, 2022), and apoptosis (Xu et al., 2017; Zhou et al., 2017).

Protein ubiquitination requires three different enzymes: E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin ligases (Heap et al., 2017; O'Connor and Huibregtse, 2017). E1 enzymes activate the ubiquitin polypeptide in an ATP-dependent manner, and the activated forms are then conjugated to E2 enzymes through the formation of thioester bonds (Wang et al., 2018). Finally, E3 ubiquitin ligases recognize both E2 enzymes and specific target substrates that confer specificity to the system, and then the Ub can be transferred from E2 enzymes to the target substrates to complete the ubiquitination process (Rittinger and Ikeda, 2017; Yau et al., 2017). The coordination of E1, E2, and E3 enzymes earmarks target proteins with a wide variety of ubiquitin modifications such that distinct ubiquitin modifications transmit different cellular signals (Khaminets et al., 2016; Venuto and Merla, 2019). Specific ubiquitin-binding domains (UBDs) can identify ubiquitylated substrate proteins (Kristariyanto et al., 2015; Kung et al., 2019; Polykratis et al., 2019; Spiliotopoulos et al., 2019). UBDs utilize diverse mechanisms to interact with various surface patches on ubiquitin molecules or different ubiquitin linkages (Hicke et al., 2005; Dikic et al., 2009; Komander and Rape, 2012). The hydrophobic surfaces of ubiquitin molecules, such as isoleucine 36 (Ile36) and isoleucine 44 (Ile44), are the structural basis for the recognition of ubiquitination signals. Different ubiquitin chains have various spatial structures and thus expose different hydrophobic surfaces, which can be recognized by specific UBDs. Proteins containing UBDs recognize and transmit the functional signals represented by ubiquitin chains (Buetow and Huang, 2016). Similar to many other protein post-translational modifications (PTMs), ubiquitination can be preserved through cleavage by deubiquitylating enzymes (DUBs) (Herhaus and Sapkota, 2014; Nishi et al., 2014; Clague et al., 2019) (Figure 1).

FIGURE 1

The versatility of ubiquitination is determined by the complex assembly pattern of ubiquitin molecules on the target protein. Ubiquitins can be attached to one or multiple lysine residues with either a single ubiquitin molecule (mono- and multi-mono-ubiquitination, respectively) or ubiquitin polymers (poly-ubiquitination) (Eger et al., 2010; Akutsu et al., 2016; Chitale and Richly, 2017; van der Heden van Noort et al., 2017). Poly-ubiquitin chains comprising only one single linkage are often assumed to be homotypic (Jeusset and McManus, 2017; Leestemaker and Ovaa, 2017), whereas heterotypic chains adopt multiple linkages within the same polymer (branched or non-branched) (Akturk et al., 2018). In a poly-ubiquitin chain, ubiquitin moieties can be linked through any of the seven lysine residues (K6, K11, K27, K29, K33, K48, and K63) or N-terminal methionine (Met1) (Dittmar and Winklhofer, 2019; Spit et al., 2019; Liao et al., 2022), resulting in an almost unlimited number of poly-ubiquitin chain topologies (Varadan et al., 2004; Sadowski and Sarcevic, 2010; Dondelinger et al., 2016; O'Connor and Huibregtse, 2017; Padala et al., 2017). Further complexity is added to ubiquitination when the ubiquitin polypeptide is modified by phosphorylation (Dong et al., 2017) or acetylation (Choudhary et al., 2009; Ohtake et al., 2015). Given the sophisticated assembly of protein ubiquitination, it has been often referred to as the “ubiquitin code” (Komander and Rape, 2012). Proteomics studies have shown that Lys48-linked chains are predominant in cells (>50% of all linkages), and Lys63-linked chains rank the second abundant chain form, however, researchers have begun to characterize the remain chain types, which were considered to be “atypical” ubiquitin modifications (linked through Lys6, Lys11, Lys27, Lys29, Lys33 and Met1) (Xu et al., 2009; Dammer et al., 2011; Kim et al., 2011; Wagner et al., 2011; Ziv et al., 2011).

1.2 Structural Features of Poly-Ubiquitin Chains

Poly-ubiquitin chains occur when a single ubiquitin molecule is repeatedly connected in series with another ubiquitin lysine residue. Substrate proteins can be distinguished by poly-ubiquitin chains by attaching between different types of deubiquition formations, single mono-ubiquitination events, multiple mono-ubiquitinations events, homotypic ubiquitination events and heterotypic ubiquitination events (branched and non-branched ubiquitination) (Sokratous et al., 2014; Yau and Rape, 2016; Zhao et al., 2017). This also led to the formation of eight different homotypic chains. The key distinguishing feature of how this can be achieved is the specific combination of E2/E3 enzymes, thereby triggering distinct cellular fates of substrate proteins. However, some of the reported E2/E3 enzyme combinations were not 100% specific for targeted linkage. It has been reported that two E1 enzymes were selected for ubiquitin in humans: UBA1 and UBA6 (Barghout and Schimmer, 2021). Humans also encoded 40 E2 conjugation enzymes cooperate with approximately 600 E3 ligase enzymes (Hodson et al., 2014). The E3s were categorized into three groups: RING/U-box, HECT, and RING between RING (RBR) (Wang et al., 2020).

With the assistance of E1, E2, and E3, mono-ubiquitination occurs when a single ubiquitin is attached to its target proteins, then Ub molecules are added to the model in linear ways one by one (Torres et al., 2009; Tang et al., 2011). The sequential addition model of Ub on the substrate contributes to the elongation of the Ub lines. When secondary Ub molecules are connected to specific lysine residues, they are called homotypic chains. If any of the attached adjacent Ub molecules are linked to each other by different lysine residues (mixed or branched model), a heteropic structure is formed. For homotypic chains, reports have found that different chain types are closely related to the confirmation of the structure, either “compact” or “open”. Generally, non-proteolytic ubiquitination Lys63 linkages and Met1 linkages, adopt “open” ones. Contrast to the aforementioned linkages, internal structural molecules interact with each other among degradable linkages, like Lys6, Lys11 and Lys48 linkages, and those linkages display “open” conformation. Furthermore, all ubiquitin moieties can be modified by acetylation or phosphorylation to add additional layers of complexity (Kane et al., 2014; Kazlauskaite et al., 2014; Koyano et al., 2014; Ordureau et al., 2014; Ohtake et al., 2015; Swaney et al., 2015) (Figure 1).

Numerous studies have found that ubiquitin acetylation inhibits poly-ubiquitination elongation, and phosphoubiquitin leads to mitophagy. Any PTM chain can be changed to ubiquitin chains, which may prevent or facilitate ubiquitin interactions. Protein phosphorylation is linked to ubiquitination for proteasomal degradation. Reports have shown that the phosphorylation of ULK1 by MAPK1/3 kinase interacts with BTRC, which leads to subsequent proteasomal degradation and attenuates breast cancer bone metastasis (Deng et al., 2020). However, the stability of some proteins is also regulated by phosphorylation. Reports have also shown that Aurora B-mediated phosphorylation of ubiquitin specific protease 13 (USP13) at Serine 114 promoted the stability of Aurora B.

1.3 Encoding and Decoding the Ubiquitin Code

Encoding and decoding the ubiquitin code is performed by factors that recognize Ub chains and connect the substrate proteins to the downstream response (Ji and Kwon, 2017; Kwon and Ciechanover, 2017). Recognition of chains occurs through discrete domains and affinity binders with specificity for a particular Ub substrate and chain type (Fu et al., 2012; Suryadinata et al., 2014; Kniss et al., 2018; Michel et al., 2018). This complex system consists of the conjugation of diverse mono, multi-mono and polymeric chains (Rösner et al., 2015; Ji and Kwon, 2017). The interpretation of how, when, and why the ubiquitin codes are written, read, and erased emerged to be characterized. Ubiquitination is a powerful decoration process of proteins and is typically actualized by “ubiquitinase” (Zientara-Rytter and Subramani, 2019). Ubiquitin can be successfully linked to one of the seven lysine residues, all of which can be characterized as poly-ubiquitin chains (Laplantine et al., 2009; Regev et al., 2015; Bax et al., 2019). Poly-ubiquitin chains with different topologies depended upon the lysine residues (which were chosen to be attached) and the substantial chain length, determine the lucky chance of the target proteins and regulate diverse cellular processes, known as “ubiquitin code” (Dittmar and Selbach, 2017; Chatr-Aryamontri et al., 2018; Fottner et al., 2019; O'Donnell, 2019; Song and Luo, 2019). Recent discoveries have deepened our understanding of the whole picture of the ubiquitin code, the interplay between “writers” (E1/E2/E3s), “erasers” (DUBs) and “readers” (ubiquitin binding domain containing proteins) (Tanno and Komada, 2013; Heride et al., 2014; Rogerson et al., 2015; Di Lello and Hymowitz, 2016; Smeenk and Mailand, 2016). Studies have highlighted that mono-ubiquitination can be catalyzed by different E2 and E3 enzymes, acting either individually or together to determine specific substrates. Notably, the linkage specificity of E3s containing RING or U-box domains is likely dictated by E2. As for the HECT E3s class of enzymes, HECT domain swaps can activate the acceptor lysine and are sufficient to determine the linkage specificity. RBR E3s, however, are somewhat complex. RBR E3s display linkage specificity in multiple chains, Met1-, Lys63-, Lys48-, and Lys27-linked chains, as well as mono-ubiquitination, while cooperating with E2 to synthesize Lys-linked or Met1-linked chains. The Ub tag attached to a certain substrate, which is preferably achieved through the cooperation of specific E2/E3 enzyme pairs, represents a complex yet specific message encoded by the cell (Kim and Huibregtse, 2009; David et al., 2011; Turek et al., 2018). Interestingly, this is achieved by Ub receptors which are equipped with one or more UBDs (Mattern et al., 2019). Ubiquitin recognition achieved by UBDs can translate written code into specific outcomes. There are more than 20 families of UBDs that bind to different patches on Ub surrounding hydrophobic patches, either lle44 or lle36 (Dikic et al., 2009; Hendriks et al., 2018). Moreover, UBDs are able to sense unique 3D conformations of distinct chain types, which are associated with diverse biological activities, meaning that this small motif-containing protein can help recognize versatile signals and affect the desired effect (Lee et al., 2006; Penengo et al., 2006; Reyes-Turcu et al., 2006; Bomar et al., 2010). In addition, ubiquitin-interacting proteins which served as “decoders” of the ubiquitin message, participated in the downstream regulation of the ubiquitinated substrate (Heideker and Wertz, 2015; Leznicki and Kulathu, 2017; Mevissen and Komander, 2017). These “decoders” may specifically reverse the ubiquitination process or function as receptors for the transfer of the targeted substrate toward downstream signaling components and/or subcellular compartments (Hu et al., 2002; Lin et al., 2008; Komander et al., 2009). To date, 55 ubiquitin specific proteases (USPs), 14 ovarian tumor DUBs (OTUs), 10 JAMM family DUBs, 4 ubiquitin C-terminal hydrolases (UCHs) and 4 Josephin domain DUBs have been identified. Encoding and decoding ubiquitin codes are responsible for all levels of epigenetic changes, and by changing substrate protein activities, they can also activate and repress effects on gene transcription depending on their target proteins and the ubiquitin chain types, all of which are connectively related to the process of tumor proliferation (Kim and Baek, 2006; Zheng et al., 2008; Fradet-Turcotte et al., 2013; Yeh et al., 2018). Ubiquitin code signaling is frequently dysregulated in numerous cancer types and can function as a tumor suppressor or tumor promoter, suggesting a potential target for cancer therapy (Loch and Strickler, 2012; Choudhry et al., 2018; Emanuelli et al., 2019).

1.4 Physiological Functions of Non-proteolytic Poly-Ubiquitin Chains

The simplest version of ubiquitination or mono-ubiquitination confers non-degradative activities including protein localization (Yang et al., 2017), endocytosis (Shih et al., 2002; Windheim et al., 2008), trafficking, DNA repair (Xie et al., 2014; Whiteaker et al., 2018), autophagy (Chen S. et al., 2017; Zheng et al., 2020; Leng et al., 2021) and chromatin remodeling (Cole et al., 2021). When mono-ubiquitination is further modified, multiple lysine residues of the substrate are yielded to induce multi-mono-ubiquitination. Emerging investigations have found that this process connects ubiquitin with subcellular trafficking (Yin et al., 2010; Cooray et al., 2011) and immune-suppressive functions (Zhu et al., 2018). As for poly-ubiquitination, Lys48-linked poly-ubiquitination leads to the degradation of substrates (Komander and Rape, 2012). In contrast, Lys63-linked poly-ubiquitination exerts critical signaling functions in regulating protein stability, including nuclear factor κB (NF-κB) signaling (Syed et al., 2006; Wu Z. et al., 2014; Gallo et al., 2014), endocytosis (Galan and Haguenauer-Tsapis, 1997), DNA damage responses, and immune responses (Wu and Karin, 2015; Hrdinka et al., 2016; Liu et al., 2017; Paul and Wang, 2017). Emerging experiments have shown that incorrect regulation of cellular processes (either tumour inhibitors or promoters) contributes to cancer pathogenesis and progression (Shirane et al., 1999). Additionally, the cellular functions of atypical ubiquitin linkages (except Lys11-linked ubiquitin) are supposed to be non-degradable (Kulathu and Komander, 2012; Iwai, 2014, 2015; Meza Gutierrez et al., 2018) and in most cases, activities involved in Lys63-linked poly-ubiquitin chains are also considered to be non-degradable (Liu et al., 2015).

Of note, other chains also regulate specific physiological functions: Lys6-linked poly-ubiquitin was supposed to be indirectly linked to DNA damage response with the help of heterodimeric ubiquitin E3 ligase BRCA1–BARD1 (Wu-Baer et al., 2003; Wu-Baer et al., 2010). Linear (M1) chains can regulate NF-κB activation (Behrends and Harper, 2011; Chen et al., 2015; Borghi et al., 2018), whereas Lys11 linkage acts as a powerful degradation signal in heterotypic ubiquitin conjugates (Locke et al., 2014; Mevissen et al., 2016) and lys27 linkage can prompt mitochondrial depolarization and mediate translocation of the E3 ligase Parkin, which accumulates Lys27-linked linkages on mitochondrial protein voltage-dependent anion-selective channel protein1 (VDAC1). This exact Lys27-linked translocation leads to Parkinson’s disease in the presence of Parkin (Geisler et al., 2010; Glauser et al., 2011). Lys27 linkage has also been demonstrated to be related with the DNA damage response and innate immune response (Xue et al., 2018). The propagation of Wnt/β-catenin signaling through Lys29-or Lys11-linked ubiquitin chains is closely associated with cancer pathogenesis and is involved in protein ubiquitination at multiple levels (Hay-Koren et al., 2011). Several studies have reported the functions of both Lys29-and Lys33-linked chains in the regulation of AMPK-related protein kinases (Al-Hakim et al., 2008), and the Lys33 linkage is negatively regulated by T-cell antigen receptors (TCRs), which indirectly affect cellular activities in tumors (Huang et al., 2010). In this review, we will focus on recent progresses in non-degradable ubiquitin chains in tumorigenesis and the essential proteins involved in non-proteolytic ubiquitination.

2 The Roles of Non-Proteolytic Ubiquitination in Tumorigenesis

Non-proteolytic ubiquitination, including both mono-ubiquitination and poly-ubiquitination (mainly K6-, K27-, K29-, K33-, K63-, and M1-linked poly-ubiquitination), has become key regulators in a variety of cancers. How they function as signaling entities in the pathogenesis and progression of cancer will be beneficial to gain an in-depth understanding of ubiquitination (Figure 2).

FIGURE 2

2.1 Mono-Ubiquitination

Mono-ubiquitination has been suggested to be even more dynamic than previously thought, and its functions have been deciphered by various ubiquitin-binding proteins. It has been demonstrated that the cellular functionality of ubiquitin is mediated by mono-ubiquitin and/or poly-ubiquitin. In fact, mono-ubiquitination is associated with tumorigenesis, not limited to membrane transportation, endocytosis, receptor internalization, degradation in lysosomes, and protein reprocessing (Haglund et al., 2003). BMI1 interacts with histone H2A through mono-ubiquitination, repressing multiple genes, such as INK4A/ARF, which function in the pRb and p53 pathways, thereby facilitating cancer progression (Lin et al., 2015). Interestingly, in the presence of UbE2E1, PRC1 catalyzes the mono-ubiquitination of H2A, contributing to cancer cell proliferation (Wheaton et al., 2017). Mono-ubiquitination is also involved in the process of USP22 regulating histone H2B and exhibits both oncogenic and tumor-suppresser roles in cancer development (Jeusset and McManus, 2017). In addition, reversible mono-ubiquitination activity plays an essential role in balancing TGF-β/SMAD signaling, which is involved in cancer initiation and progression (Xie et al., 2014). Mono-ubiquitination also regulates forkhead box O (FOXO) proteins, which control specific gene expression programs that are vital for slowing the onset of cancer in aging individuals (Greer and Brunet, 2008). Strikingly, FANCL cooperates with, UBE2T and catalyzes mono-ubiquitination, which participated in the regulation of Fanconi Anemia pathway, leading to chromosome instability and promoting tumorigenesis (Machida et al., 2006; Hodson et al., 2014; Miles et al., 2015; Sun et al., 2020; Wang S. et al., 2021) (Table 1, 2).

2.2 Linear (M1) Linkage

2.2.1 The LUBAC Complex Encodes the M1 Linkage

Emerging evidences connect Met1-linked ubiquitin chains to NF-κB signaling, which enables physiological regulation of inflammation and immune responses (Emmerich et al., 2011; Borghi et al., 2018). Indeed, mutations and deficiencies involved in the formation and dissolution of Met1-linked poly-ubiquitin chains have been extensively illustrated in immune-related disorders (Tokunaga and Iwai, 2012; Fiil et al., 2013; Fiil and Gyrd-Hansen, 2014). Until now, linear ubiquitin chain assembly complex (LUBAC) is the only known E3 ubiquitin ligase assembling this type of chain (Kirisako et al., 2006; Walczak et al., 2012). The multi-subunit E3 ligase comprises catalytically active hybrid organic-inorganic perovskite (HOIP, also known as RNF31) and two adaptor proteins, HOIP1L (also known as RBCK1) and SHANK-associated RH domain-interacting protein (SHARPIN) (Tokunaga et al., 2011). Both HoIL-1 and SHARPIN can co-operate with HOIP, which might be a central part of the LUBAC complex (Ikeda et al., 2011; Elton et al., 2015). The HOIP orthologue, linear ubiquitin E3 ligase (LUBEL), modifies Kenny with M1-linked linear ubiquitin chains in Drosophila and is indispensable for inflammatory responses by activating Imd pathway (Aalto et al., 2019). Additionally, HOIP, with the help of cIAP1, is recruited to the linear ubiquitination of the TNFR2 signaling complex and activates canonical NF-κB, thereby facilitating cancer progression (Borghi et al., 2018). Multiple investigations found that HOIP, presumably through M1-linked ubiquitination, was proved to be connected with sorts of malignancies, including breast and prostate cancer (Guo et al., 2015; Zhu et al., 2016). Furthermore, previous experiments highlight that HOIL-1 interacts with HOIP, which adds a Mi-linked poly-ubiquitin chain to specific NF-κB signaling proteins, suggesting its link to a diversity of immune disorders, antiviral signaling (Elton et al., 2015), iron and xenobiotic metabolism (Elton et al., 2015), apoptosis (Emmerich et al., 2011; Lewis et al., 2015; Sasaki and Iwai, 2015), and cancer (Queisser et al., 2014; Taminiau et al., 2016). Another member of the LUBAC family, SHARPIN, is a novel component of the LUBAC complex. Spontaneous mutation of this tiny gene led to dysregulation of the NF-κB signaling pathway through linear ubiquitinate of NEMO (the key modulator of NF-κB). This systematic linear ubiquitination is obvious and can induce immune system disorders in SHARPIN-deficient mice (Tokunaga et al., 2011). Interestingly, SHARPIN-containing complexes can also interact with NEMO to activate NF-κB pathway (Ikeda et al., 2011). Moreover, NEMO was identified to be modified by LUBAC, generating M1-linked chains that were recognized by the UBAN domain of NEMO, causing conformational changes in the intertwined helices of NEMO dimers (Haas et al., 2009; Belgnaoui et al., 2012; Tokunaga and Iwai, 2012; Noad et al., 2017). NF-κB signaling regulates human cellular activities in different ways and is balanced by ubiquitination and deubiquitination (Adhikari et al., 2007; Lork et al., 2017) (Table 2).

2.2.2 OTULIN Dissembles M1-Linked Poly-Ubiquitin Chains

OTULIN, a methionine 1 (M1)-specific deubiquitinase (DUB), is a rare member of the OTU family of DUBs. Its proximal ubiquitin moiety cannot break down isopeptide linkages of ubiquitin chains, but can efficiently cleave peptide bonds present in the linear chains (Keusekotten et al., 2013; Rivkin et al., 2013). OTULIN presents negative regulation in the cellular process of immune homeostasis and inflammation (Damgaard et al., 2019). Depletion of OTULIN resulted in an increase in the formation of linear Ub chains and demonstrated proteasome dysregulation as the cause of NF-κB positive activation, which in turn restricts bacterial proliferation (Takiuchi et al., 2014; van Wijk et al., 2017). Moreover, the deficiency of OTULIN led to the inability to remove M1-linked poly-ubiquitin signals, which are typically conjugated by the LUBAC, resulting in LUBAC degradation and dysregulation of TNF signaling and cell death (Tokunaga, 2013; Damgaard et al., 2016). Notably, the function of LUBAC is controlled by cylindromatosis (CYLD), which interacts with the LUBAC core subunit HOIP to generate Met1-linked ubiquitin. However, this interaction can be weakened by the Met1-Ub-specific deubiquitinase OTULIN. In addition, through the deubiquitinase function of OTULIN, LUBAC can regulate Met1-Ub to ensure an advisable response to innate immune activity (Elliott et al., 2016; Hrdinka et al., 2016). The CYLD/TRAF3 complex has also been reported to regulate NF-κB-mediated inflammation and interferon signaling, which defines a subset of head and neck cancers that harbor human papillomavirus (Chen T. et al., 2017). Notably, accumulating evidence has manifested that linear ubiquitin chains play essential roles in ensuring appropriate activity of inflammatory responses and innate immune signaling (Tokunaga and Iwai, 2012; Tokunaga, 2013; Jing et al., 2017). The linear ubiquitination of cFLIP is directly induced by RNF31, a catalytic subunit of LUBAC, at Lys-351 and Lys-353, contributing to TNFα-induced apoptosis, thereby protecting cells from apoptosis (Tang et al., 2018) (Table 3).

2.2.3 Linear Ubiquitination in Tumorigenesis

M1-linked ubiquitination, specifically N-terminal Met1-linked ubiquitination, is able to form eight different inter-ubiquitin linkages via its N-terminal methionine (M1). It can be specifically catalyzed by LUBAC. For instance, EGFR recruits PKP2 to the plasma membrane and cooperates with LUBAC (HOIP), activating linear ubiquitination of NEMO, which is critical for tumor cell proliferation (Hua et al., 2021). Also, Epsins 1/2 promotes NEMO linear ubiquitination via LUBAC, driving breast cancer development (Song et al., 2021). Moreover, LUBAC (SHARPIN) regulated β-catenin activity through linear ubiquitination, promoting gastric tumorigenesis (Zhang et al., 2021). Interestingly, OTULIN exclusively cleaves M1-linked ubiquitination and exhibits a high affinity for linear ubiquitination. LUBAC and linear ubiquitination have been found to be relevant to TNF signaling. Interestingly, OTULIN was shown to remove linear ubiquitination from LUBAC-modified proteins, which is critical for various cellular activities (Draber et al., 2015). Moreover, the deubiquitinating enzyme, CYLD, was also identified for disassembly Met1-linked-Ub (mostly the immune system). A previous report demonstrated that modification of proliferating cell nuclear antigen (PCNA) induces apoptosis and inhibits tumor growth through the linear ubiquitin chain (Qin et al., 2018).

2.3 Lys63 Linkage

2.3.1 The Writer Enzymes for the Lys63 Linkage

It has been well established that Lys63 chains (ubiquitin chains topology lysine 63 poly-ubiquitin linkages) regulate and trigger distinct cellular signaling, including kinase activation, signal transduction, protein trafficking, endocytosis and DNA repair (Spence et al., 1995; Hofmann and Pickart, 1999; Komander and Rape, 2012; Wu and Karin, 2015; Hrdinka et al., 2016). The E2 conjugating enzyme complex Ubc13/Uev1A preferentially assembles the K63-pUb chain (Smith et al., 2013; Zhang et al., 2018). Furthermore, Tax can be recruited to K63-pUb by E3 ligase RNF8 and Ubc13/Uev1A, which allows the activation of TGFβ-activating kinase 1 (TAK1), followed by multiple downstream signaling pathways such as the IKK and JNK pathways. These ultimately lead to DNA damage repair, cytokinesis, and the genomic instability in ATL cells (Ho et al., 2015; Lee et al., 2017). Similarly, tumor necrosis factor receptor associated factor 6 (TRAF6) can interact with the E2 conjunction enzyme Ubc13/Uev1A in a RING-dependent manner, catalyzing Lys63-linked TRAF6 auto-ubiquitination. This activates IKK and NF-κB, thereby promoting TAK1 and IKK to trigger spontaneous osteoclast differentiation (Lamothe et al., 2007a; Lenoir et al., 2021). Another report also showed that TRAF6, in a RING-dependent fashion, catalyzed auto-ubiquitination by conjugating with ubc13/Uev1A, activating the AKT pathway, and promoting cell migration in breast cancer (Lamothe et al., 2007b; Niu et al., 2021).

The Ubc13/Uev1A complex has been shown to conjugate Lys63-linked poly-ubiquitination of substrate proteins, which contribute to breast cancer metastasis via NF-кB signaling regulation (Wu Z. et al., 2014; 2017). It is also reported that Ubc13 can catalyze K63-linked protein poly-ubiquitination, which is indispensable for the activation of non-SMAD signaling by TAK1 and p38, whose activity controls breast cancer metastatic spread and lung colonization (Wu X. et al., 2014). Interacting with Ubc13, RNF213 mediates autoubiquitination and controls inflammatory responses and angiogenic activities (Habu and Harada, 2021). RNF8 was demonstrated to activate Ubc13 and recruit K63-linked poly-ubiquitin conjugation to histones H2A/H2AX, thus contributing to breast cancer predisposition (Vuorela et al., 2011). Moreover, RNF8 utilizes the RING domain, mediating Lys63-linked Ub chains, which is required for DNA double-strand break (DSB) signaling and the downstream BRCA1 tumor suppressor recruitment or lung cancer cell proliferation (Hodge et al., 2016; Xu et al., 2021). Inhibiting the Ubc13/Uev1A complex specifically, which is critical for Lys63-linked ubiquitination, promotes ubiquitin conjugation at the Lys147 site, thereby upregulating NF-кB signaling in multiple myeloma and other cancers (Gallo et al., 2014). UbcH6 and NEDD4 regulate angiogenesis and tumor growth (Sun et al., 2021). Ube2w accompanies the E3 ligase RNF4 function in distinct DNA repair pathways through Lys63-linked chains and BRIC6 (also named BRUCE) acting on K63-linked ubiquitinylate in unstimulated cells, which regulates the DNA double-strand break response through bridging USP8 and BRCT-repeat inhibitor of hTERT expression (BRIT1) in a deubiquitination manner (Ge et al., 2015; Maure et al., 2016). Poly-ubiquitination of histone H1 depends on Ubc13 and RNF8, which prolong pre-existing ubiquitin modifications to K63-linked chains, thereby stimulating RNF8-Ubc13 mediated DNA damage response (Mandemaker et al., 2017). SKP2 triggers non-proteolytic K63-linked ubiquitination, which is crucial for cancer initiation and progression by positively regulating cancer cell survival and glycolysis. The depletion of SKP2 restricts cancer stem cell proliferation and survival (Chan et al., 2013). However, the non-proteolytic K63-linked ubiquitination triggered by SKP2 can be reversed and modulated by debiquitinase ovarian tumor domain-containing protein 1 (OTUD1) (Yao et al., 2018) and USP10 (Liao et al., 2019). USP10 has been identified as a novel deubiquitinase of SKP2 that modulates and stabilizes SKP2. Indeed, USP10 can recognize and remove Lys63-linked ubiquitin chains from Bcr-Abl, leading to positive activities in chronic myeloid leukemia cells. OTUD1 interacts with p53 and is essential for constant stabilization of p53. Its overexpression dramatically induces the cell cycle and apoptosis (Mevissen et al., 2013; Piao et al., 2017). In addition, several more DUBs have been defined as having linkage specificity for Lys63-linked ubiquitination. CYLD, a tumor suppressor, inhibits NF-κB signaling by cleaving K63-linked ubiquitination of NEMO/IKKγ, thus reducing its stability and averting the IKK complex from phosphorylation of IκB (Chen T. et al., 2017). Furthermore, CYLD was associated with the catalytic LUBAC subunit HOIP to counteract Lys63-Ub and Met1-Ub conjugation to receptor-interacting protein kinase 2 (RIPK2), leading to restriction of innate immune signaling and cytokine production (Hrdinka et al., 2016). TRAF-binding protein domain (TRABID) was demonstrated to bind and cleave Lys63-linked ubiquitin moieties on APC tumor suppressor substrates, which led to the disruption of APC and activation of Wnt signaling in colorectal cancer cell lines (Tran et al., 2008). The USP17/TRAF2/TRAF3 complex acts to stabilize its client proteins, enhancing inflammatory responses and stemness in lung cancer cells (Lu et al., 2018). USP20 deubiquitinates TRAF6 and Tax, and may function as a key regulator of adult T cell leukemia (ATL) leukemogenesis through suppressing NF-κB activation (Yasunaga et al., 2011). In terms of actively removing Lys63-linked poly-ubiquitin chains on GβL, OTUD7B appears to be the primary regulator in governing mTOR2 integrity, which is essential for NF-κB activation in cancer biology (Wang B. et al., 2017). Further detailed analysis of Lys63-linked ubiquitination is required to better understand how ubiquitin chains function in numerous cellular events. However, identification of this linkage will provide an ideal point to understand the potential mechanism in the cellular regulation of the incoming ubiquitin research (Table 1, 2).

2.3.2 Disassembly of Lys63 Poly-Ubiquitin Chains by DUBs

Although a number of DUBs have been identified, the disassembly ability of the substrate and its physiological role, especially for Lys63 poly-ubiquitin chains, is poorly defined. Previous studies have shown that K63-specific DUBs, A20, and CYLD present the anti-tumor effects by regulating NF-κB signaling (Heyninck and Beyaert, 2005; Sun, 2010; Meng et al., 2021; Zhu et al., 2021). USP10 reduces K63-linked ubiquitination chains and functions as a tumor suppressor (He et al., 2021). Stimulated by the pro-inflammatory cytokine TNF, A20 exerts two major functions: sequential de-ubiquitination and catalyzing receptor-interacting protein (RIP), resulting in downregulation of NF-κB signaling. Absence of A20 led to hyper-accumulation of Lys63 poly-ubiquitin in NF-κB signaling. Like A20, CYLD disassembles the Lys63 poly-ubiquitin recruiting signal and degrades IKKκ. In this way, USP4 and OTUD1 cleaves K63-linked ubiquitination chains, and regulates downstream NF-κB signaling (Fan et al., 2011; Liang et al., 2013; Wu et al., 2022) (Table 3).

2.3.3 The Multifaceted Functions of Lys63 Poly-Ubiquitin Chains in Cancer

Lys63-linked chains have been described as non-degradative signals and are the core of inflammatory system and the NF-κB pathway, which is involved in either mono-ubiquitination or poly-ubiquitination. TGFβ type I receptor (TBRI) was shown to interact with TRAF6 through Lys63-dependent poly-ubiquitination in order to promote tumor invasion (Mu et al., 2011). It has also been reported that polo-like kinase 1 (PLK1) phosphorylates kruppel-like factor 4 (KLF4), leading to the recruitment of TRAF6, resulting in Lys63-linked ubiquitination and promoting nasopharyngeal tumorigenesis (Mai et al., 2019). Moreover, TRAF6 functions in hepatocarcinogenesis by regulating TRAF6/HDAC3/c-Myc signal axis. Mechanistically, TRAF6 interacts with histone deacetylase 3 (HDAC3) via Lys63-linked ubiquitin chains, which enhances c-Myc stability, and its overexpression has been proposed to facilitate HCC progression (Wu et al., 2020). Similarly, HUWE1 promotes K63-linked ubiquitinatination of c-Myc, thereby promoting retinoblastoma cell proliferation (Dai et al., 2021). It was also demonstrated that ASK1-dependent phosphorylation and lys63-linked poly-ubiquitination of LKB1 is critical for its activation. Tankyrase and RNF146 act as upstream regulators of the LKB1/AMPK pathway to promote Lys63-linked ubiquitination resulting in AMPK activation and tumor suppression (Li et al., 2019). Lys63-linked non-proteolytic ubiquitination of Hexokinase 2 by HectH9 effectively disrupts glycolysis activation and facilitates apoptosis in prostate cancer cells (Lee H. J. et al., 2019). SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) methylates Akt and functions as a scaffold to recruit JMJD2A, which then binds TRAF6 and Skp2-SCF to the Akt complex, thereby promoting tumor development in lung cancer (Wang et al., 2019). Notably, numbers of E3 ligase have been discovered to catalyze K63-linked ubiquitination chains, which are involved in activating NF-κB or Akt signaling pathway, acting as tumor promoters and facilitating tumor progression (Ji et al., 2021; Xu et al., 2021; Yu et al., 2021; Zhou et al., 2021; Zhu et al., 2021; He et al., 2022). Lys63 poly-ubiquitin chains were also found to be involved in driving the cell cycle and promoting cancer progression (Kolapalli et al., 2021). In contrast, tripartite motif-containing 31 (TRIM31) directly ubiquitinates p53 via K63-linked ubiquitination, resulting in tumor-suppressing effects (Guo et al., 2021) (Table 2).

2.4 Lys6 Linkages–Tumor Suppressors

Lys6-linked ubiquitin chains are less abundant in resting cells and their functional implications are unclear (Durcan et al., 2014; Michel et al., 2017). It has been reported that BRCA1 can be autoubiquitinated and then bound by UBX domain containing protein 1 (UBXN1) through K6-linked poly-ubiquitin chains. Interestingly, UBXN1 regulates BRCA1 expression upon ubiquitination. Autoubiquitinated forms of BRCA1 act as tumor suppressors and inhibit their enzymatic function (Wu-Baer et al., 2010). Moreover, BRCA1 auto-ubiquitination occurs in a way that the BRCA1/BARD1 complex conducts polymerization by conjugation with K6-linked polymers, which imparts cellular properties to its natural enzymatic substrates (Wu-Baer et al., 2003), further linking BRCA1 auto-ubiquitination to the tumor suppressor. C terminus HSC70-interacting protein (CHIP) was reported to bind to fas-associated protein with death domain (FADD) to induce K6-linked poly-ubiquitination of FADD, which was demonstrated to be essential for the prevention of cell death (Seo et al., 2018).

It has also been revealed that community-based learning collaborative (CBLC) assembles K6- and K11-linked poly-ubiquitin on EGFR and positively regulates its stability. The sustained activation of EGFR is largely dependent on CBLC-mediated ubiquitination, and its dysregulation is preferentially destined for membrane recycling, which plays an important role in non-small-cell lung carcinoma (NSCLC) progression (Hong et al., 2018).

Structural findings indicated that USP30 efficiently cleaves Lys6-linked Ub chains, which abrogates parkin-mediated Ub-chain formation in mitochondria. Dysfunction of this novel distal Ub-recognition mechanism is associated with physiological disorders such as hepatocellular carcinoma (Sato et al., 2017; Wang et al., 2022). Although an extraordinary progress has been made over the last 2 decades, the detailed functional consequences of Lys6 modifications require further investigation (Tables 2, 3).

2.5 Lys27 linkages—emerging Tumor Promoter

Emerging investigations have demonstrated that K27-linked poly-ubiquitination is crucial for promoting cancer development, such as facilitating cell proliferation, invasion, and metastasis (Peng et al., 2011; Yin et al., 2019). ITCH, an E3 ubiquitin ligase, was shown to generate Lys27-linked poly-ubiquitination of the transcription factor TIEG1, which inhibits TIEG1 nuclear translocation and subsequent Treg development (Peng et al., 2011). Additionally, TGF-β, in the presence of cytokine IL-6, can efficiently promote mono- and poly-ubiquitination of TIEG1 and modulate Treg/Th17 differentiation (Peng et al., 2011). Yet, it seems that tumor immunity in TIEG1^−/− mice were apparently enhanced by hampering Treg development and increasing Th17 response, suggesting its pro-tumor effects (Peng et al., 2011). In the presence of proinflammatory cytokines, ITCH can catalyze BRAF to disrupt 14–3–3-mediated inhibition of BRAF kinase activity, resulting in ΜEK/ERK signaling activation. This ubiquitin function plays an essential role in supporting the proliferation and invasion abilities of melanoma cells (Yin et al., 2019). Another report connected Lys27-linked ubiquitination to melanoma cell invasive properties, in which HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1) decorated fibronection with Lys27 Ub moieties (El-Hachem et al., 2018). As mentioned in this study, upregulation of fibronectin in turn modulates the transcription levels of integrin subunit alpha V (ITGAV) and integrin β1 (ITGB1), leading to an increased invasive power of melanoma cells (El-Hachem et al., 2018). TRAF4 was found to increase TrkA kinase activity through K27- and K29-linked ubiquitination upon nerve growth factor (NGF) stimulation, followed by the recruitment of downstream adaptor proteins and increased metastasis in prostate cancer (Singh et al., 2018).

Strikingly, reports have also revealed that Lys27-linked ubiquitination is implicated in the DNA damage response (DDR) and innate immunity. A previous study demonstrated that RNF168 can target the N-terminal tail of histones H2A/H2A.X, generating Lys27-linked ubiquitin chains. In response to DNA damage, K27 ubiquitination is the major source of PTMs that mark chromatin. Meanwhile, the activition of DDR can be inhibited by mutation of K27, which hinders the localization of 53BP1 and BRCA1 to DDR foci (Gatti et al., 2015). DDR is responsible for the recognition, signal transduction and repair of DNA damage. The inactivation of DDR will result in the accumulation of cell mutations and the increase of genomic instability, which play an essential role in cancer initiation (Klinakis et al., 2020). It is also indicated that K27 and the related DDR mediators may be the potential targets for the development of anti-tumor drugs. cGAS is subjected to K27 poly-ubiquitination by RNF185, facilitating cGAS-mediated innate immune response. TRIM-mediated ubiquitination by binding to residue K27 activates TBK1 recruitment to mitochondrial antiviral signaling (MAVS) and promotes innate immunity (Wang Q. et al., 2017). TRIM31 and TRIM40 can also mediate K27-linked ubiquitination, thereby regulating innate and adaptive immunity (Wang X. et al., 2021; Shen et al., 2021). Specifically, TRIM40 interacts with Riok3, resulting in RIG-I and MDA5 degradation through K27-linked ubiquitination, and negatively regulates innate immunity (Shen et al., 2021). Nevertheless, TRIM31 catalyzes K27-linked ubiquitination of SYK, facilitating antifungal immunity (Wang X. et al., 2021). Additionally, auto-ubiquitination of TRIM23 through K27-linked ubiquitination was found to mediate autophagy via activation of TBK1 (Sparrer et al., 2017). Moreover, E3 ubiquitin ligase Hectd3 decorates Stata3 with non-degradative K27-linked poly-ubiquitin chains and Malt1 with K27/K29-linked poly-ubiquitin chains, leading to signaling-related ubiquitination in neuroinflammation (Cho et al., 2019) (Table 3). In fact, the innate immune system plays a key role in the formation of tumor. The response of it is generally affected by a variety of immune cells and cytokines in tumor microenvironment (Wenbo and Wang, 2017). In this way, it is beneficial to clarify the regulatory effects of K27 on tumor innate immunity for understanding the mechanisms of cancer.

2.6 Lys29 and Lys33 linkage—possible Tumor Promoters

Recent proteomic data have identified the role of Lys29-and Lys33-linked ubiquitin chains in various biological processes, including the control of AMPK-mediated mitochondrial function and Wnt-induced transcription signaling (Jiang et al., 2015; Nusse and Clevers, 2017). AMPK-related kinases, AMPK-related kinase 5 (ARK5, also known as NUAK1) and microtubule-affinity-regulating kinase 4 (MARK4), which are mediated by unconventional Lys29/Lys33 linkage, are involved in cell polarity and proliferation (Al-Hakim et al., 2008). One of the underlying mechanisms is that USP9X specifically identifies Lys29/Lys33-conjugated ubiquitin chains on NUAK1 and MARK4 (Al-Hakim et al., 2008). However, it should be noted that the ubiquitination of NUAK1 and MARK4 suppresses their phosphorylations rather than restores their stability and facilitates LKB1 activation. Interestingly, the TRABID core domain N-terminal Npl4-like zinc finger (NAZF1) preferentially hydrolyzes K29/K33-linked diUb, and this novel AnkUBD displays TRABID linkage specificity (Licchesi et al., 2011). Additionally, TRABID interacts with APC tumor suppressor protein, recruits TCF target genes, and activates their transcription in colorectal cancer cells (Tran et al., 2008). The OUT family DUB TRABID preferentially abolishes Smad ubiquitination regulatory factor 1-induced K29/K33-linked poly-ubiquitin chains from UV radiation resistance associated gene (UVRAG), thereby promoting autophagosome maturation and inhibiting cell proliferation in hepatocellular cancer (Feng et al., 2019). Considering its linkage specificity, it would be insightful to explore the potential positive regulation of TRABID in cancer tumorigenesis via these two pathways.

K29-linked ubiquitin chains play important roles in driving cancer invasion and metastasis, as well as in the positive regulation of immunity (Singh et al., 2018; Cho et al., 2019; Gao et al., 2021). Several studies have also manifested that, with the assistance of Cbl-b and ITCH, T cell receptor-zeta (TCR-zeta) was decorated with a K33 linage, accompanied by positively activated T cells and immune responses (Huang et al., 2010). In addition, OTUD1 directly deubiquitinates the inhibitor SMAD7 of TGF-β pathway and aborates Lys33-linked poly-ubiquitin chains, which inhibits cell stemness and suppresses metastasis (Zhang et al., 2017). Acetylation of GLDC inhibits its enzymatic activity and facilitates K33-linked ubiquitination by NF-X1, thereby suppressing glioma tumor growth (Liu et al., 2021). Ultimately, Lys29-and Lys33-linked ubiquitin chains appear to have more complicated cellular functions that remain to be characterized (Table 2, 3).

2.7 Mixed Linkage and Branched Poly-Ubiquitination

Mixed linkage chains send mixed signaling messages that can be identified by different linkage-specific receptors. Our understanding of the mixed linkages and branched poly-ubiquitin is limited. Previous reports have elucidated that Tax in combination with UbcH2, Uhc5c, or UbcH7, can catalyze the construction of free mixed-linkage poly-ubiquitin chains, which are responsible for IKK-NF-κB activation and induction of T cell transformation (Wang et al., 2016). Furthermore, Brcc 36 isopeptidase complex (BRISC), the JAMM/MPN + family of DUBs, preferentially cleaves K63 linkages within mixed-linkage chains. In addition, RING1B was found to generate atypical mixed poly-ubiquitin chains and mediate mono-ubiquitination of H2A (Ben-Saadon et al., 2006). A recent study showed that SPOP triggered mixed-linkage ubiquitination of MyD88 in human lymphoma cells and mouse HSCs, suggesting that the SPOP-MyD88 pathway plays a critical role in hematopoietic neoplasms (Jin et al., 2020).

3 Conclusion and Furture Perspectives

Non-proteolytic ubiquitination, the molecular switch in cell fate regulation, plays a crucial role in post-translational protein modifications. Diverse ubiquitination enzymes are essential for ubiquitination linkages that are necessary for normal metabolism and physiological functions. Meanwhile, it is also the root cause of physiological disorders, such as cancer. The aberrant regulation of the UPS is typically achieved by ubiquitination enzymes, DUBs, 20S proteasome catalytic core particles and 19S proteasome regulatory particles (Rape, 2018). In general, specific ubiquitination enzymes determine ubiquitin linking with one of the seven lysine residues to form distinctive styles of poly-ubiquitin chains, deciding the fate of substrate proteins. It is noteworthy that the ubiquitin proteasome system functions as a theoretical target for drug screening, and the study of ubiquitination will provide more insights into the development of anti-tumor drugs. Recently, the quantities of E3s inhibitors have already been processed in preclinical models of cancer immunotherapy. It has been shown that E3 enzyme Smac mimetics (SMs) were the promising immune modulators for cancer therapy as the antagonists targeting E3 ligases IAPs (Cossu et al., 2019). The small molecule inhibitor AMG-232, targeting another E3-ubiquitin ligase oncogenic mouse double minute 2 homolog (MDM2), was shown to strengthen T cell killing of cancer cells, especially when combined with an anti-PD-1 monoclonal antibody (Sahin et al., 2020). Several other proteasome inhibitors have been confirmed to be clinically effective against malignancies as well. The neddylation (NAE) inhibitor pevonedistat has already been tested in multiple clinical trials and has shown positive effects in patients with AML or advanced solid tumors (Barghout and Schimmer, 2021). Small molecule inhibitors based on deubiquitinase have been widely used in experimental anti-tumor therapy, most of which are still in the preclinical research stage. Due to dose-limiting toxicity, the first deubiquitinase inhibitor VLX1570 was terminated in the clinical trial phase. No other deubiquitinase inhibitors have been approved for clinical studies since then. Also, the discovered deubiquitinase inhibitors related to tumor treatment are mainly concentrated in the USP family, and the relationship between the inhibitors of non-USP family members and the treatment of malignant tumors needs to be further studied (Zhang et al., 2022). Interestingly, the innovative approaches of proteolysis targeting chimeras (PROTACs) and molecular glues might facilitate clinical cancer therapy (Cruz Walma et al., 2022; Kung and Weber, 2022; Zhou and Xu, 2022). Consequently, it is essential further to investigate the role of ubiquitination enzymes in tumorigenesis. Meanwhile, targeting different ubiquitination, including K6-, K27-, K29-, K33-, K63-, and M1-linked poly-ubiquitination, may also be one of the directions for cancer drug discovery. Although great progresses have been achieved with the development of anti-cancer drugs aimed at the UPS, numerous challenges still stand in the way. Some candidate inhibitors have emerged as drug resistant or have limited efficacy in patients. Despite these questions, the discovery of new drugs targeting single or multiple segments of the UPS is still worthy of future research.

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