GO:1990381 ubiquitin-specific protease binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:1990381 (ubiquitin-specific protease binding) is a molecular function describing the selective binding of a protein to a ubiquitin-specific protease (USP) or deubiquitinase.
• This binding event is central to deubiquitination-dependent signaling, including TBK1 stabilization in cardiac remodeling and AMPKα2 regulation in diabetic cardiomyopathy.
• USP family members such as USP38, OTUD1, USP4, USP5, USP24, USP42, and OTUD3 are established binders or scaffolds in this GO term.
• Dysregulated ubiquitin-specific protease binding contributes to cancer, metabolic disease, infection, and inflammatory conditions.
• CRISPR knockout, point-mutation, knock-in, and overexpression models are essential to dissect whether a candidate binder is causal or correlative.
• EDITGENE provides end-to-end CRISPR cell model and library screening services to study GO:1990381-related mechanisms.
Description
GO:1990381, ubiquitin-specific protease binding, is a molecular function term that captures the physical interaction between a protein and a ubiquitin-specific protease (USP), also known as a deubiquitinase. This binding event is not merely a passive association; it often determines substrate selection, catalytic activation, or spatial sequestration of the protease, thereby shaping ubiquitin-dependent signaling. Because ubiquitin-specific proteases regulate the stability, localization, and activity of key signaling proteins, the binding partners that engage them are critical nodes in cellular homeostasis. Researchers study this term to understand how deubiquitination is targeted, how disease-associated mutations disrupt these interactions, and how to therapeutically modulate them. The term is therefore highly relevant to cancer biology, metabolic disorders, cardiovascular disease, and host-pathogen interactions.
ubiquitin-specific protease binding At A Glance
| GO ID | GO:1990381 |
|---|---|
| GO term | ubiquitin-specific protease binding |
| Ontology | molecular_function |
| Synonym | deubiquitinase binding; deubiquitinating enzyme binding |
| Major function | Selective physical interaction with a ubiquitin-specific protease (USP), influencing deubiquitination targeting and signaling |
| Example binders | USP38, OTUD1, USP4, USP5, USP24, USP42, OTUD3 |
| Disease relevance | Cardiac remodeling, diabetic cardiomyopathy, periodontitis, bladder cancer, EV71 infection, hepatocellular carcinoma, osteogenic differentiation, metabolic stress |
| Research methods | Co-immunoprecipitation, proximity labeling, CRISPR KO/point mutation/knock-in, overexpression, library screening |
What Is GO:1990381?
According to the QuickGO definition, GO:1990381 is the binding to a ubiquitin-specific protease. In practical terms, it describes any protein-protein interaction in which one molecule selectively recognizes and physically associates with a USP-family deubiquitinase. This function is distinct from being a substrate of the protease; it is about the binding event itself, which can recruit, inhibit, or activate the protease.
Why Is ubiquitin-specific protease binding Important in Cell Biology?
Ubiquitin-specific protease binding is important because it dictates which proteins are deubiquitinated, when, and where. This function controls the half-life and activity of signaling molecules such as TBK1, AMPKα2, RAB7A, Twist1, c-Myc, and others. Consequently, alterations in these binding events can drive cancer progression, metabolic dysfunction, inflammatory bone loss, and viral pathogenesis. Understanding GO:1990381 helps researchers identify therapeutic targets and design precise CRISPR models to test causality.
• Controls deubiquitination of key signaling proteins such as TBK1 and AMPKα2.
• Regulates autophagy-lysosome fusion through RAB7A deubiquitination.
• Promotes cancer progression by stabilizing oncoproteins like Twist1 and c-Myc.
• Modulates host response to viral infection, e.g., EV71 restriction of TBK1 K63-polyubiquitination.
• Impacts osteogenic differentiation of human adipose-derived stem cells.
• Links nutritional stress to metabolic homeostasis via OTUD3.
• Provides a mechanistic basis for drug discovery targeting USP-substrate interfaces.
• Enables CRISPR-based functional genomics to distinguish causal binders from bystanders.
Molecular Mechanism of ubiquitin-specific protease binding
Recognition and Binding to USP Domains
In simple terms: A protein finds and sticks to a deubiquitinase.
Ubiquitin-specific proteases contain catalytic domains and accessory domains that mediate protein-protein interactions. Binders often engage the USP via short linear motifs or folded interfaces, as seen for USP38 stabilizing phospho-TBK1 and OTUD1 directly binding AMPKα2. This binding can be constitutive or signal-induced, and it determines substrate specificity.
Substrate Selection and Deubiquitination
In simple terms: The binder helps the deubiquitinase choose which protein to edit.
Once bound, the USP can remove ubiquitin chains from the target. For example, OTUD1 deubiquitinates AMPKα2 to modulate mitochondrial function, while USP4 depletion leads to RAB7A hyperubiquitylation and impaired autophagosome-lysosome fusion. The binding event thus directly influences downstream ubiquitin signaling.
Stabilization or Destabilization of Signaling Complexes
In simple terms: Binding can protect or destroy a protein complex.
USP38 binding stabilizes phospho-TBK1, aggravating pathological cardiac remodeling. In contrast, USP24 restricts K63-linked polyubiquitination of TBK1 during EV71 infection, altering antiviral signaling. These examples show that GO:1990381 can have context-dependent outcomes.
Cofactors and Post-Translational Modifications
In simple terms: Other modifications can switch the interaction on or off.
Phosphorylation of TBK1 is required for USP38 binding, and METTL5-mediated translation of USP5 affects c-Myc stability. Such modifications add layers of regulation to ubiquitin-specific protease binding.
Regulation by Cellular Stress and Metabolism
In simple terms: Stress and nutrients change how binders and USPs interact.
OTUD3 regulates metabolic homeostasis in response to nutritional stresses, and USP42 influences osteogenic differentiation. These findings indicate that GO:1990381 is dynamically regulated by environmental cues.
Key Genes Involved in GO:1990381 ubiquitin-specific protease binding
The following genes encode proteins that bind to or function as ubiquitin-specific proteases in the context of GO:1990381, based on verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| USP38 | Stabilizes phospho-TBK1 | Cardiac remodeling |
| OTUD1 | Deubiquitinates AMPKα2 | Diabetic cardiomyopathy |
| USP4 | Regulates RAB7A ubiquitylation | Periodontitis and autophagy |
| USP5 | Stabilizes Twist1; translation regulated by METTL5 | Bladder cancer and hepatocellular carcinoma |
| USP24 | Restricts K63-linked polyubiquitination of TBK1 | EV71 infection |
| USP42 | Regulates osteogenic differentiation | Adipose-derived stem cells |
| OTUD3 | Regulates metabolism under nutritional stress | Metabolic homeostasis |
| TBK1 | Substrate stabilized by USP38; targeted by USP24 | Cardiac remodeling and antiviral signaling |
| AMPKα2 | Substrate deubiquitinated by OTUD1 | Mitochondrial function |
| RAB7A | Substrate affected by USP4 depletion | Autophagosome-lysosome fusion |
| Twist1 | Substrate stabilized by USP5 | Bladder cancer progression |
| c-Myc | Substrate stabilized via USP5 translation | Hepatocellular carcinoma |
| METTL5 | Facilitates USP5 translation | Glucose metabolism reprogramming |
| USP38 | Binds and stabilizes phospho-TBK1 | Pathological cardiac remodeling |
| OTUD1 | Directly binds AMPKα2 | Diabetic cardiomyopathy |
| USP4 | Binds and regulates RAB7A | Periodontitis |
| USP5 | Binds and stabilizes Twist1 | Bladder cancer |
How Is ubiquitin-specific protease binding Regulated?
The binding of proteins to ubiquitin-specific proteases is regulated at multiple levels. Phosphorylation of TBK1 is required for USP38 binding, and METTL5-mediated translation of USP5 controls c-Myc stability. Nutritional stress regulates OTUD3 function, while USP42 modulates osteogenic differentiation in a context-dependent manner. These examples indicate that GO:1990381 is not static but responsive to cellular signals.
ubiquitin-specific protease binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| USP38 | Pathological cardiac remodeling | Cardiomyocyte-specific knockout or point-mutation knock-in |
| OTUD1 | Diabetic cardiomyopathy | Cardiomyocyte overexpression or knockout |
| USP4 | Periodontitis | USP4 knockout in periodontal cells |
| USP5 | Bladder cancer | USP5 overexpression or knockout in bladder cancer cell lines |
| USP24 | EV71 infection | USP24 knockout or overexpression in infected cells |
Cardiovascular and Metabolic Disease
USP38 binding to phospho-TBK1 aggravates pathological cardiac remodeling, and OTUD1 deubiquitination of AMPKα2 drives diabetic cardiomyopathy. These findings link GO:1990381 to heart failure and metabolic dysfunction.
Cancer
USP5 stabilizes Twist1 to promote bladder cancer progression, and METTL5-mediated USP5 translation stabilizes c-Myc in hepatocellular carcinoma. Thus, ubiquitin-specific protease binding can support oncogenic signaling.
Inflammatory and Infectious Disease
USP4 depletion impairs autophagosome-lysosome fusion and aggravates periodontitis, while USP24 restricts TBK1 polyubiquitination during EV71 infection. These studies highlight roles in inflammation and host-pathogen interactions.
Metabolic and Differentiation Disorders
OTUD3 regulates metabolic homeostasis under nutritional stress, and USP42 influences osteogenic differentiation of human adipose-derived stem cells. Dysregulation may contribute to metabolic and bone-related disorders.
From ubiquitin-specific protease binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Is USP38 required for TBK1 stabilization? | USP38 knockout cardiomyocytes |
| Does OTUD1 directly deubiquitinate AMPKα2? | OTUD1 knockout or point-mutation knock-in |
| How does USP4 loss affect autophagy? | USP4 knockout cells |
| Does USP5 binding to Twist1 drive cancer? | USP5 overexpression and knockout |
| Can USP24 restrict EV71 replication? | USP24 knockout or overexpression |
| Does OTUD3 regulate metabolic stress? | OTUD3 knockout or tagged knock-in |
How to Study the ubiquitin-specific protease binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Co-IP | Physical protein-protein interaction | Detect USP38-TBK1 binding |
| Proximity labeling | Spatially restricted interactome | Identify OTUD1-AMPKα2 interaction |
| CRISPR knockout | Loss-of-function phenotype | Test USP4 role in autophagy |
| Overexpression | Gain-of-function phenotype | Study USP5 stabilization of Twist1 |
| Ubiquitin remnant profiling | Site-specific ubiquitylation changes | Analyze USP24 effects on TBK1 |
| Ribo-seq | Translational efficiency | Measure METTL5-dependent USP5 translation |
| RNA-seq | Transcriptional changes | Assess USP42 effects on differentiation |
Co-Immunoprecipitation and Proximity Labeling
Co-IP and proximity labeling (e.g., BioID) can detect physical binding between a candidate protein and a USP, as demonstrated for USP38 and phospho-TBK1 and OTUD1 with AMPKα2.
CRISPR Functional Genomics
CRISPR knockout, point-mutation, and knock-in models allow causal testing of binding interfaces. For example, USP4 knockout impairs autophagy, and USP5 overexpression stabilizes Twist1.
Proteomics and Ubiquitin Chain Analysis
Mass spectrometry-based ubiquitin remnant profiling can quantify changes in substrate ubiquitylation upon USP binding, as shown for USP24 and TBK1 and OTUD3 under stress.
Transcriptomic and Translational Profiling
RNA-seq and Ribo-seq can reveal downstream effects of USP binding, such as METTL5-mediated USP5 translation affecting c-Myc and USP42 effects on osteogenic differentiation.
How CRISPR Can Be Used to Study GO:1990381 ubiquitin-specific protease binding
Knockout
CRISPR knockout of a USP or its binding partner can abolish the interaction and reveal downstream phenotypes, such as USP4 depletion impairing autophagy or USP38 loss reducing TBK1 stabilization.
Point Mutation
Point mutations at the binding interface can dissociate binding without affecting catalytic activity, allowing precise structure-function studies, as seen for phospho-TBK1 mutants that fail to bind USP38.
Knock-in
Knock-in of tagged or mutant alleles (e.g., HA-tagged OTUD1) enables endogenous-level interaction studies and localization, as used for OTUD1 and AMPKα2.
Overexpression
Overexpression of a USP or binder can drive disease phenotypes, such as USP5 overexpression stabilizing Twist1 in bladder cancer or USP24 overexpression restricting EV71 replication.
How EDITGENE Supports ubiquitin-specific protease binding Research
Researchers studying ubiquitin-specific protease binding-related genes often need to determine whether a candidate gene is causally involved in a specific pathway or disease. EDITGENE provides validated CRISPR cell models and screening services to answer these questions with rigor.
Contact EDITGENE today to design your custom CRISPR model for ubiquitin-specific protease binding research.
Frequently Asked Questions About ubiquitin-specific protease binding
What is GO:1990381?
GO:1990381 is the molecular function of binding to a ubiquitin-specific protease, also called deubiquitinase binding.
What genes are involved in ubiquitin-specific protease binding?
Genes include USP38, OTUD1, USP4, USP5, USP24, USP42, and OTUD3, among others.
How does ubiquitin-specific protease binding affect disease?
It can stabilize or destabilize signaling proteins, contributing to cardiac remodeling, cancer, metabolic disease, and infection.
What is the difference between a USP and a deubiquitinase?
A USP is a subclass of deubiquitinase; all USPs are deubiquitinases, but not all deubiquitinases are USPs.
Which diseases are linked to USP38 binding?
USP38 binding to phospho-TBK1 aggravates pathological cardiac remodeling.
How is OTUD1 involved in diabetic cardiomyopathy?
OTUD1 directly deubiquitinates AMPKα2 and induces mitochondrial dysfunction.
What role does USP4 play in periodontitis?
USP4 depletion impairs autophagosome-lysosome fusion and aggravates periodontitis.
Can CRISPR be used to study ubiquitin-specific protease binding?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are widely used.
What methods detect ubiquitin-specific protease binding?
Co-immunoprecipitation, proximity labeling, and proteomics are common methods.
What services does EDITGENE offer for GO:1990381 research?
EDITGENE offers knockout, point mutation, knock-in, overexpression cell models, CRISPR library screening, and bioinformatics.
Conclusion
GO:1990381, ubiquitin-specific protease binding, is a fundamental molecular function that governs deubiquitination-dependent signaling in health and disease. The verified literature highlights its roles in cardiac remodeling, diabetic cardiomyopathy, periodontitis, cancer, infection, and metabolic stress. By combining precise CRISPR models with functional genomics, researchers can dissect these interactions and identify new therapeutic targets.
References
- 1. Xiao Z et al.. 2024. Ubiquitin specific protease 38 aggravates pathological cardiac remodeling by stabilizing phospho-TBK1.. Int J Biol Sci 20(5):1815-1832 PMID: 38481817
- 2. Han X et al.. 2025. Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 and inducing mitochondrial dysfunction.. Nat Commun 16(1):6668 PMID: 40683882
- 3. Kang S et al.. 2025. USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis.. Autophagy 21(4):771-788 PMID: 39663592
- 4. Cai H et al.. 2024. Ubiquitin-specific protease 5 promotes bladder cancer progression through stabilizing Twist1.. Oncogene 43(10):703-713 PMID: 38218898
- 5. Zang L et al.. 2023. Ubiquitin-specific protease 24 promotes EV71 infection by restricting K63-linked polyubiquitination of TBK1.. Virol Sin 38(1):75-83 PMID: 36334706
- 6. Xia P et al.. 2023. METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression.. Cancer Commun (Lond) 43(3):338-364 PMID: 36602428
- 7. Pan Y et al.. 2024. [Ubiquitin-specific protease 42 regulates osteogenic differentiation of human adipose-derived stem cells].. Beijing Da Xue Xue Bao Yi Xue Ban 56(1):9-16 PMID: 38318890
- 8. Zhou N et al.. 2022. Deubiquitinase OTUD3 regulates metabolism homeostasis in response to nutritional stresses.. Cell Metab 34(7):1023-1041.e8 PMID: 35675826
