OTU deubiquitinases as immune-circuit editors: from human immunopathology to therapeutic prioritization

Abstract

OTU deubiquitinases are linkage-sensitive ubiquitin editors that regulate immune circuits, human immunopathology, and emerging therapeutic opportunities. By remodeling K48-, K63-, and linear ubiquitin chains, they control protein stability, scaffold assembly, and signal amplitude across nuclear factor κB (NF-κB), and tumor-immune pathways. Individual OTUs have been linked to inflammation, infection, autoimmunity, metabolic dysfunction, and cancer, yet disease-by-disease descriptions often obscure their shared mechanistic logic. We therefore organize current evidence around chain selectivity, substrate context, and immune-circuit function. We examine innate inflammatory regulation, adaptive and tumor immunity, and the emerging therapeutic landscape, including covalent inhibitors, engineered binders, repurposed compounds, and induced-proximity platforms. We also distinguish catalytic from non-catalytic functions, define determinants of context dependence, and propose practical criteria for translational target ranking. This framework positions OTU enzymes not only as an isolated catalogue of disease factors, but also as a mechanistically coherent field centered on mechanism-guided target ranking and disease-specific biological context.

1 Introduction

Ubiquitination is a highly versatile post-translational modification that regulates protein turnover, signal assembly, intracellular trafficking, and stress adaptation. Its biological consequences are determined by the presence of ubiquitin conjugation. Other factors include the topology of ubiquitin chains, including degradative and non-degradative linkages that encode distinct signaling outputs (1–3). Deubiquitinases (DUBs) therefore function not merely as passive erasers of ubiquitin, but as active editors of signaling specificity.

Among the DUB families, ovarian tumor (OTU) domain-containing enzymes are of particular interest because many members exhibit substantial ubiquitin-chain selectivity and are deeply embedded in immune and inflammatory signaling networks (4–7). By editing K48-, K63-, and linear ubiquitin chains, OTU enzymes can terminate signaling by dismantling activating ubiquitin scaffolds. They also can preserve signaling by removing degradative ubiquitin marks from key effectors. This dual logic places the OTU family at a strategic interface between molecular signal decoding and disease biology.

Over the past decade, accumulating evidence has linked OTU enzymes to a broad disease spectrum, including inflammatory disorders, infection, autoimmunity, neuroinflammatory conditions, metabolic dysfunction, and cancer (5, 8–12). In oncology, OTU enzymes have emerged as regulators of tumor growth, invasion, stress adaptation, and immune escape. In immunology, they are increasingly recognized as linkage-sensitive rheostats that shape innate inflammatory amplitude, antiviral responses, and the balance between protective and pathological immunity. At the same time, the field is entering a translational phase, with early inhibitors, engineered binders, and repurposed compounds beginning to define the druggability of selected OTU targets (5, 8–12).

The literature is extensive but fragmented across individual enzymes and disease categories. Across these settings, OTU enzymes converge on a limited set of signaling programs, including nuclear factor κB (NF-κB), stimulator of interferon genes (STING), mitogen-activated protein kinase (MAPK), Wnt/β-catenin, cell death, and tumor–immune crosstalk. Organizing the field around these shared circuits provides a clearer basis for comparing context-dependent functions and therapeutic opportunities. Recent OTUD-focused syntheses have updated cancer and antiviral biology (13).

The present review emphasizes immune-circuit editing, human immunopathology, and translational target ranking. We first examine how OTU enzymes decode ubiquitin-chain topology and achieve signal selectivity. We then discuss innate inflammatory regulation, adaptive and tumor immunity, and the main barriers to therapeutic translation. Figure 1 presents the conceptual framework, and Tables 1, 2 summarize representative disease mechanisms and the inhibitor landscape, respectively.

Figure 1

2 Ubiquitin chain editing and signal selectivity of OTU enzymes

A defining property of the OTU family is that its members are not functionally redundant. Instead, they differ in catalytic architecture, accessory domains, substrate-recognition modes, and ubiquitin-linkage preference (4, 5, 14). This biochemical diversity enables OTU enzymes to function as pathway-selective regulators rather than generic suppressors of ubiquitination. In biological terms, OTU-dependent deubiquitination can either dampen signaling by removing non-degradative activating chains or stabilize signaling proteins by counteracting K48-linked proteasomal targeting. The structural and domain-level heterogeneity of OTU family members is summarized in Figure 2.

Figure 2

Related catalytic cores do not imply interchangeable functions. Non-redundancy is imposed by linkage preference, stimulus-dependent recruitment, subcellular localization, lineage-specific expression, and substrate access. These features place individual OTUs in distinct molecular neighborhoods and time windows, limiting functional interference even when catalytic chemistry is shared (4, 5). This distinction is central to interpreting the seemingly divergent functions of OTU enzymes across diseases. When an OTU removes K48-linked ubiquitin chains from an oncogenic transcription factor, stress-response protein, or signaling intermediate, it prolongs protein half-life and may amplify disease-driving programs. By contrast, when it removes K63- or linear ubiquitin chains from receptor-associated scaffold proteins or inflammatory signaling complexes, it can attenuate signal propagation and restore homeostatic control (2, 4, 7, 15). The biological outcome of OTU activity is therefore determined by at least three interacting parameters: chain type, substrate identity, and cellular context.

At the systems level, a relatively small set of signaling axes repeatedly emerges as OTU-sensitive. These include NF-κB-associated inflammatory complexes, STING-dependent innate immune signaling, MAPK and AKT pathways, Wnt/β-catenin signaling, cell death regulators, and proteins that shape redox adaptation or immune checkpoint biology (7, 16–19). This recurrent convergence suggests that OTU enzymes should not be conceptualized as isolated enzyme–substrate pairs, but as a family of ubiquitin editors that repeatedly regulate a limited number of biologically decisive signaling hubs.

Apparent contradictions usually reflect context rather than inconsistency. An OTU that terminates receptor-proximal inflammatory signaling in an immune cell may stabilize an oncogenic or immune-evasive protein in a stressed tumor cell. The relevant unit of analysis is therefore the enzyme–substrate–cell-state combination, not the enzyme alone. Thus, OTU family unity lies in a shared logic of linkage-sensitive editing, whereas biological output is determined by recruitment and substrate context. This framework underpins the immune and cancer sections below.

3 OTUs in innate immune and inflammatory programs

The most conceptually mature area of OTU biology lies in innate immune and inflammatory signaling. Multiple family members function as regulators of receptor-proximal ubiquitin editing. They control signal amplitude, duration, and resolution during inflammatory activation (16, 20, 21). OTU enzymes often behave as rheostats that calibrate the balance between protective host defense and pathological tissue injury.

A20 remains the canonical example. A20 is a multifunctional regulator with both deubiquitinase-related and ubiquitin-binding activities. It is central to the containment of excessive inflammatory signaling, particularly along NF-κB-associated pathways (22–25). Its importance extends beyond basic signaling biology: maintaining immune tolerance and preventing persistent inflammatory damage. A20 represents one of the demonstrations that defective ubiquitin editing can translate into systemic immune dysregulation. Recent clinical synthesis extends the spectrum of A20 haploinsufficiency (HA20) toward lupus-like autoimmunity. This emphasizes that A20 deficiency is relevant not only to autoinflammatory phenotypes but also to monogenic lupus-spectrum disease with renal, cutaneous, and systemic manifestations (26).

OTU deubiquitinase with linear linkage specificity (OTULIN) provides a complementary paradigm by controlling linear ubiquitin homeostasis and thereby safeguarding inflammatory balance at the level of linear ubiquitin chain assembly complex (LUBAC)-associated signaling (6, 7, 9, 27, 28). While A20 is mainly related to inflammatory restraint, OTULIN highlights the importance of linkage-specific editing in the quality of downstream immune output. Together, A20 and OTULIN establish a central principle: OTU enzymes are not merely enzymes acting downstream of inflammation, but active architects of inflammatory signal fidelity. Recent data also expand OTULIN-associated disease beyond canonical OTULIN-related autoinflammatory syndrome (ORAS), showing that heterozygous OTULIN haploinsufficiency can underlie trigger-dependent necrosis. These findings reinforce the clinical importance of linear-ubiquitin control in human inflammatory pathology (29).

Beyond these archetypal regulators, a broader set of OTU enzymes participates in more context-dependent innate immune programs. OTUD1 and OTUD5, for example, have been implicated in inflammatory activation, tissue injury responses, and stress-responsive signaling. YOD1 and selected OTUB family members appear to fine-tune disease-associated inflammatory states (16–19, 21, 30–32). OTU enzymes frequently operate at signaling bottlenecks where immune activation intersects with cell survival, barrier function, and tissue remodeling. Recent work has further extended OTUD1 biology to neuroinflammation. OTUD1 deubiquitinates and stabilizes C/EBPβ in microglia, amplifying inflammatory responses and worsening Alzheimer-related pathology. OTUD5-linked biology has expanded beyond interferon-centered models. A macrophage extracellular vesicle (EV)–GBP2-OTUD5-glutathione peroxidase 4 (GPX4) axis has been shown to drive endothelial ferroptosis and barrier injury in sepsis-induced acute lung injury (33, 34). OTUD5 illustrates how regulatory plasticity can create therapeutic entry points beyond direct inhibition. Phosphorylation of Ser177 is required for catalytic activation, while mTOR-dependent phosphorylation connects OTUD5 activity to nutrient-responsive mTORC1/2 signaling. Recruitment to specific complexes further changes substrate access. Upstream kinases, interaction surfaces, and turnover pathways may therefore be tractable even when a selective OTUD5 inhibitor is unavailable (35, 36).

Context dependence is determined by the substrate available to the OTU, the cell lineage and subcellular compartment, the intensity and duration of the initiating stimulus, and the surrounding metabolic or redox state (24, 37–40). During acute Tumor necrosis factor (TNF) or Toll-like receptor (TLR) signaling, A20 recruitment to ubiquitin-rich receptor complexes promotes resolution and protects tissue. In chronic inflammation or a hypoxic, therapy-stressed tumor, the dominant substrate pool may instead favor stabilization of survival, repair, or immune-evasion proteins. OTUD1 similarly restrains Receptor-interacting serine/threonine-protein kinase 1 (RIPK1)–NF-κB signaling in colitis yet can increase platinum sensitivity by destabilizing the RAD23 homolog B (RAD23B)/XPC repair complex. Protective or pathogenic labels are therefore meaningful only when cell state, substrate, and disease phase are specified (22–25).

A similar principle applies to acute inflammatory injury, antiviral signaling, and inflammasome-associated contexts. Emerging work indicates that OTU-mediated ubiquitin editing may influence not only cytokine output, but also cell fate decisions, including survival, apoptosis-related signaling, and inflammatory tissue remodeling. These observations reinforce the notion that OTU enzymes are best understood as signal-integrating regulators rather than isolated inflammatory modifiers. Representative OTU-mediated control of canonical inflammatory and antiviral pathways is illustrated in Figure 3 (16–19, 21, 30). OTU enzymes therefore occupy proximal control points that couple innate signaling to cell fate and tissue injury. Representative immune and disease associations are summarized in Table 1.

Figure 3

Additional lineage-specific examples are summarized in Supplementary Figure 1. It highlights OTU-dependent signaling in Natural killer (NK) cells, neutrophils, mast cells, dendritic cells, and stem-cell-associated inflammatory niches. Representative mechanistic evidence for these lineage-specific roles includes A20-dependent regulation of mast cell and dendritic cell activation thresholds (22–25), OTULIN-mediated control of Linear ubiquitin chain assembly complex (LUBAC)-associated signaling in myeloid lineages (6, 7, 9, 28), and OTUD family contributions to innate immune cell survival and effector function (31, 32). Representative non-neoplastic disease contexts are summarized in Supplementary Figure 2, which links recurrent OTU-dependent mechanisms to intestinal inflammation, acute lung injury, rheumatoid arthritis, systemic lupus erythematosus, neuroinflammation, and metabolic disease (24, 25, 28, 31, 32, 37–40).

4 OTUs in adaptive immunity and tumor immune remodeling

The contribution of OTU enzymes to cancer is most productively understood through common malignant programs. In solid and hematologic malignancies, OTU enzymes mainly influence three processes: maintenance of proliferative and survival signaling, promotion of invasion and phenotypic plasticity, and modulation of tumor–immune interactions (41–46).

First, several OTU family members stabilize proteins that support tumor growth and survival. OTU domain-containing ubiquitin aldehyde-binding proteins (OTUB) and other members have been linked to the preservation of oncogenic effectors, transcriptional regulators, metabolic proteins, or pathway intermediates that collectively sustain proliferation and stress tolerance (42, 47–49). Although the specific substrates differ across models, the mechanistic logic is consistent: OTU-mediated removal of degradative ubiquitin chains increases protein stability and reinforces signaling output. These have been reported in breast, lung, colorectal, liver, and hematologic cancers (Table 1).

Second, OTU enzymes contribute to metastatic behavior and treatment adaptation. By stabilizing proteins involved in epithelial–mesenchymal transition, extracellular matrix remodeling, redox homeostasis, and cytoskeletal plasticity, they can promote invasion, migration, and resistance to hostile microenvironmental conditions (50–55). In this setting, OTU enzymes should not be viewed solely as growth regulators. Rather, they function as facilitators of tumor adaptability, enabling malignant cells to tolerate therapeutic stress, sustain invasive phenotypes, or exploit inflammatory niches within the tumor microenvironment. In non-small cell lung cancer (NSCLC), OTUD1 enhances cisplatin sensitivity by destabilizing the RAD23B/XPC nucleotide-excision-repair complex, directly linking OTU biology to platinum response. OTUD4 has likewise emerged as a K63-linkage-selective suppressor of the Transforming growth factor-beta-activated kinase 1 (TAK1) signalosome that restrains TNF-induced NF-κB signaling and inflammation-driven oncogenesis. The same period also expanded OTUB1 biology in cancer, linking OTUB1 to ferroptosis-associated colorectal cancer progression through GPX4 stabilization and to anoikis resistance/metastasis through Protein phosphatase 1 alpha (PP1α) stabilization (54, 56–58).

Third, OTU enzymes appear to intersect with tumor immunity. Available evidence suggests that they can influence inflammatory tone within tumors, the stability of immune-relevant proteins, antigen-processing-associated pathways, and checkpoint-related signaling (59–62). This places OTU enzymes at the interface between cell-intrinsic oncogenic signaling and cell-extrinsic immune remodeling. This interface opens the possibility that OTU targeting could reshape tumor immunogenicity or sensitize tumors to immunotherapy. Representative OTU-dependent oncogenic programs across major cancer contexts are summarized in Figure 4.

Figure 4

OTU-dependent immune remodeling operates at several levels. OTUB2-mediated stabilization of programmed death-ligand 1 (PD-L1) directly weakens cytotoxic T-cell activity, whereas OTUD4/CD73 signaling and OTUD5-driven M2 polarization create adenosine-rich and myeloid-suppressive niches that favor T-cell exhaustion. OTU control of NF-κB, STING, and interferon signaling may also alter dendritic-cell maturation, inflammatory licensing, and the transcriptional environment required for major histocompatibility complex (MHC) class I antigen presentation. Direct evidence that individual OTUs regulate peptide loading or MHC-I turnover remains limited, and this distinction should be preserved (60, 63–65). These microenvironmental effects are relevant to checkpoint blockade and chimeric antigen receptor T-cell (CAR-T) therapy because persistent antigen exposure, inhibitory ligands, suppressive myeloid cells, and metabolic stress constrain T-cell fitness. Direct evidence that OTU manipulation improves CAR signaling, CAR-T persistence, or exhaustion reversal is currently sparse. OTU-directed approaches are therefore better viewed as candidate tumor-microenvironment conditioning strategies than as established CAR-T engineering targets (60, 63–65).

Beyond their tumor-intrinsic functions, OTU enzymes also operate across multiple immune-cell compartments that shape tumor-associated immunity. As shown in Figure 5, OTU family members regulate macrophage inflammatory polarization, B-cell signaling-associated survival programs, and T-cell activation or exhaustion-related pathways through control of nodes such as PD-L1, B-cell lymphoma/leukemia 10 (BCL10), RIPK3, Tumor necrosis factor receptor-associated factor 3 (TRAF3), and LUBAC-associated signaling. This cell-centered view extends the program-based framework outlined above and underscores that OTU biology in cancer should not be reduced to malignant cell-autonomous signaling alone. Instead, OTU-dependent ubiquitin editing acts across both tumor and immune compartments, thereby providing a mechanistic basis for tumor immune remodeling and potential combinatorial therapeutic intervention (59–62).

Figure 5

5 Druggability and therapeutic targeting of OTU enzymes

The translational landscape of OTU biology has evolved from conceptual interest to early-stage pharmacologic feasibility. Although no OTU-directed therapy has yet entered routine clinical application, several lines of evidence indicate that selected family members are tractable targets for small molecules, covalent inhibitors, engineered binders, and repurposed drugs (10–12, 46, 66–68).

Current strategies fall into four categories: direct small-molecule or covalent inhibitors, engineered binders such as ubiquitin variants, repurposed drugs, and induced-proximity platforms. Direct inhibitors and binders provide target-validation tools, whereas repurposed compounds offer a faster translational entry but often have uncertain selectivity (10, 46, 60, 66, 67, 69–74). DUBTAC and PRO-DUBTAC approaches remain concept-stage strategies that recruit a DUB to stabilize a protein of interest. Recent PRO-DUBTAC work demonstrates OTUB1-dependent stabilization of selected tumor-suppressive E3 ligases, but it does not yet establish a clinically deployable OTU-selective platform (75).

Therapeutically relevant OTU functions are not always catalytic. A20 is recruited to ubiquitin-rich signaling complexes through zinc-finger-dependent interactions and uses scaffold and ubiquitin-binding functions to organize signal termination. For such proteins, active-site inhibition may not reproduce genetic loss and may leave non-catalytic signaling intact. Disrupting ubiquitin-binding surfaces, recruitment interfaces, or disease-specific protein-protein interactions may therefore be more effective and potentially more selective than catalytic blockade alone (22, 23, 76). The inhibitor landscape remains predominantly preclinical. Most compounds are chemical probes or early leads rather than clinically mature candidates. Table 2 shows target-biology entries, biochemical or cellular probes, in vivo leads, and concept-stage platforms. To make the concept of translational target ranking more explicit, we propose five practical criteria for prioritizing OTU targets in future development:

• human genetic or clinicopathologic evidence linking the OTU to a defined disease phenotype;

• a reproducible mechanistic axis with a tractable substrate, signaling node, or immune-circuit function;

• demonstrable in vivo phenotypic impact in disease-relevant models;

• evidence of target engagement together with at least preliminary selectivity or cross-reactivity profiling;

• a biomarker-defined context in which therapeutic benefit is likely to outweigh disruption of protective homeostatic roles.

Three barriers remain (10, 12, 67, 69, 70, 72–74). First, selectivity is often incompletely established because conserved DUB catalytic architecture permits cross-reactivity, while many studies do not report broad biochemical panels, chemoproteomic profiling, or orthogonal cellular target-engagement assays. Table 2 therefore distinguishes compounds with limited or unreported cross-DUB profiling from better-characterized target-validation tools. Second, context dependence requires testing in disease-relevant immune and tissue compartments. Third, biomarker frameworks that identify likely responders remain scarce. Induced-proximity platforms add further constraints. Productive activity depends on ternary-complex geometry and cooperativity, and excessive concentrations of a bivalent compound can favor nonproductive binary complexes, producing a high-dose hook effect. These properties require concentration-response studies and direct assessment of ternary-complex formation rather than reliance on binary binding alone (73, 77).

6 Perspectives: from disease catalogs to mechanism-based translation

A central problem in the current OTU literature is structural rather than informational. The field has generated substantial mechanistic detail. But it is often distributed across isolated disease reports and enzyme-specific narratives, making it difficult to identify the recurrent principles that matter most for translation. Our synthesis suggests that OTU enzymes are best conceptualized as linkage-sensitive regulators positioned at the intersection of immune signaling, tissue adaptation, and disease progression (5, 11, 46, 68). The publication of multiple 2025–2026 OTU reviews raise the novelty threshold for broad family-wide summaries. They also increase the value of reviews that integrate recent human genetics, immune-circuit logic, and translational prioritization into a single framework (13).

This perspective yields two practical conclusions. First, the real value of OTU enzymes lies not in the implicated diseases, but in a limited set of biologically decisive pathways. These include NF-κB-centered inflammatory control, linear ubiquitin homeostasis, innate immune signal assembly, malignant protein stabilization, and tumor-immune crosstalk. Second, the translational relevance of OTU enzymes depends on context-specific prioritization. It is no longer sufficient to designate an OTU as broadly pathogenic or broadly protective. What matters is how that enzyme edits particular ubiquitin topologies in defined cellular states and whether such editing is therapeutically actionable (7, 9, 11, 19, 44, 46, 78). Taken together, linkage selectivity, recurrent pathway convergence, and increasingly tractable chemical or engineered intervention argue that the OTU family merits consideration as a distinct translational field rather than a loose collection of DUB case studies.

Context-specific prioritization is particularly important in oncology, where OTU-directed therapy may be most useful in combination with checkpoint blockade, cellular therapy, or pathway-specific agents. In inflammatory disease, the same principle requires separating OTUs that resolve injury from those that sustain pathological signaling.

Future work should therefore proceed along four parallel lines: deeper structural resolution of targetable OTU surfaces, more systematic substrate and chain-topology mapping, better integration of immune phenotyping with disease models, and biomarker-guided selection of disease contexts most likely to respond to OTU perturbation (5, 11, 12, 68, 73, 74). Such an agenda would move the field from descriptive enzymology toward clinically meaningful pathway engineering.

7 Conclusion

The OTU deubiquitinase family has emerged as a functionally specialized group of ubiquitin editors that link chain selectivity to immune control, inflammatory balance, tumor progression, and therapeutic opportunity. Although individual OTU enzymes differ substantially in substrate usage and biological context, they repeatedly converge on a limited number of signaling programs that govern inflammation, cell fate, stress adaptation, and tumor–host interaction (7, 19, 44, 78).

Current evidence supports two parallel conclusions. First, OTU enzymes are indispensable regulators of immune and disease biology whose actions are deeply context dependent. Second, their druggability is now sufficiently established to justify more systematic therapeutic development, provided that future work addresses selectivity, context-specific target validation, and biomarker-guided stratification (10, 67, 69, 70, 72). A mechanism-centered framework, rather than a catalog of isolated disease associations, therefore offers a productive path for translating OTU biology into clinically meaningful intervention. The field is now moving from descriptive enzymology toward disease-specific, mechanism-guided intervention.

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