OTUD4 Gene

HGNC Family	OTU domain containing (OTUD)
Name	OTU deubiquitinase 4
Description	Alternatively spliced transcript variants have been found for this gene. The smaller protein isoform encoded by the shorter transcript variant is found only in HIV-1 infected cells. [provided by RefSeq, Jul 2010]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence has positioned OTUD4 as a multifunctional regulator involved in diverse cellular processes. Its investigation follows on longstanding questions regarding the genetic basis of complex phenotypes such as ataxia and hypogonadism, conditions whose enigmatic origins have spurred research into novel regulatory molecules."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of DNA repair, OTUD4 plays a key non‐canonical role. Work has revealed that OTUD4 acts as a scaffold to support the deubiquitinases USP7 and USP9X in stabilizing the DNA demethylases ALKBH2 and ALKBH3—thereby promoting resistance to DNA alkylation damage and influencing cancer chemotherapy response."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Complementary studies in Drosophila homologues, which lack canonical catalytic activity, further suggest that OTUD4 may function in a deubiquitinase‐independent manner to regulate apoptosis pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPost‐translational modifications of OTUD4 add an additional layer of regulation. Phosphorylation near its catalytic domain switches its specificity to K63-linked chains, allowing OTUD4 to deubiquitinate targets such as MyD88 and thereby temper Toll-like receptor–mediated NF-κB activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In parallel, OTUD4 has been identified as an RNA-binding protein that localizes to neuronal RNA transport granules under physiological conditions and is recruited to stress granules upon cellular stress, with its depletion leading to defective granule formation and apoptotic cell death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn neurologic contexts, epigenome-wide studies have linked OTUD4 to neurodegenerative disease. Differential methylation in the OTUD4 gene correlates with increased mRNA and protein expression in frontotemporal lobar degeneration, and its co-methylation networks are enriched for genes associated with the ubiquitin system, RNA/stress granule biology, and glutamatergic synaptic signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer, OTUD4 functions in a context-dependent manner. In melanoma and triple-negative breast cancer, OTUD4 directly deubiquitinates and stabilizes Snail1, facilitating epithelial–mesenchymal transition and metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Conversely, in glioblastoma, high OTUD4 expression is associated with poor prognosis, as it interacts with and stabilizes CDK1 and FGFR1 to promote cell proliferation and MAPK pathway activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " In lung adenocarcinoma, NRF2 transcriptionally activates OTUD4 to enhance EGF deubiquitination and stability"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", whereas in clear cell renal cell carcinoma, OTUD4 functions as a tumor suppressor by stabilizing RBM47 and promoting ATF3-mediated ferroptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "David H Margolin, Maria Kousi, Yee-Ming Chan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "N Engl J Med (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1056/NEJMoa1215993"}], "href": "https://doi.org/10.1056/NEJMoa1215993"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23656588"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23656588"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yu Zhao, Mona C Majid, Jennifer M Soll, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Noncanonical regulation of alkylation damage resistance by the OTUD4 deubiquitinase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.201490497"}], "href": "https://doi.org/10.15252/embj.201490497"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25944111"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25944111"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marcell Louis, Kay Hofmann, Meike Broemer "}, {"type": "b", "children": [{"type": "t", "text": "Evolutionary Loss of Activity in De-Ubiquitylating Enzymes of the OTU Family."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0143227"}], "href": "https://doi.org/10.1371/journal.pone.0143227"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26588485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26588485"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yu Zhao, Miranda C Mudge, Jennifer M Soll, et al. "}, {"type": "b", "children": [{"type": "t", "text": "OTUD4 Is a Phospho-Activated K63 Deubiquitinase that Regulates MyD88-Dependent Signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.molcel.2018.01.009"}], "href": "https://doi.org/10.1016/j.molcel.2018.01.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29395066"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29395066"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Richa Das, Lukas Schwintzer, Stanislav Vinopal, et al. "}, {"type": "b", "children": [{"type": "t", "text": "New roles for the de-ubiquitylating enzyme OTUD4 in an RNA-protein network and RNA granules."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.229252"}], "href": "https://doi.org/10.1242/jcs.229252"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31138677"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31138677"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ronggui Qu, Zhihua Zhang, Ling Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ADGB variants cause asthenozoospermia and male infertility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Genet (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00439-023-02546-0"}], "href": "https://doi.org/10.1007/s00439-023-02546-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36995441"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36995441"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yuchen Gao, Jiaxin Tang, Xiuqing Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "OTUD4 regulates metastasis and chemoresistance in melanoma by stabilizing Snail1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.31104"}], "href": "https://doi.org/10.1002/jcp.31104"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37642406"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37642406"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Xiuqing Ma, Rui Wan, Yalei Wen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deubiquitinating enzyme OTUD4 regulates metastasis in triple-negative breast cancer by stabilizing Snail1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2023.113864"}], "href": "https://doi.org/10.1016/j.yexcr.2023.113864"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38040050"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38040050"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Mingxin Ci, Gaichao Zhao, Chongyang Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "OTUD4 promotes the progression of glioblastoma by deubiquitinating CDK1 and activating MAPK signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-024-06569-x"}], "href": "https://doi.org/10.1038/s41419-024-06569-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38429268"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38429268"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Shuming Hu, Yuan Yuan, Ruihan Yan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NRF2 regulates EGF stability through OTUD4 in lung adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2024.149798"}], "href": "https://doi.org/10.1016/j.bbrc.2024.149798"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38518721"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38518721"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Ziyao Li, Ye Tian, Huafeng Zong, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deubiquitinating enzyme OTUD4 stabilizes RBM47 to induce ATF3 transcription: a novel mechanism underlying the restrained malignant properties of ccRCC cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Apoptosis (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10495-024-01953-6"}], "href": "https://doi.org/10.1007/s10495-024-01953-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38553613"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38553613"}]}]}]}
Synonyms	HIN1, DUBA6, HSHIN1
Proteins	OTUD4_HUMAN
NCBI Gene ID	54726
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

OTUD4 has 6,695 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 107 datasets.

Click the + buttons to view associations for OTUD4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

OTUD4 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of OTUD4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of OTUD4 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of OTUD4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of OTUD4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of OTUD4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of OTUD4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of OTUD4 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of OTUD4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of OTUD4 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of OTUD4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of OTUD4 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of OTUD4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with OTUD4 protein from the CCLE Cell Line Proteomics dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of OTUD4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of OTUD4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of OTUD4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing OTUD4 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of OTUD4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Experimental Protein Localization Evidence Scores	cellular components containing OTUD4 protein in low- or high-throughput protein localization assays from the COMPARTMENTS Experimental Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with OTUD4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with OTUD4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Disease Associations	diseases associated with OTUD4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by OTUD4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with OTUD4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with OTUD4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with OTUD4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with OTUD4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at OTUD4 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of OTUD4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of OTUD4 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing OTUD4 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GDSC Cell Line Gene Expression Profiles	cell lines with high or low expression of OTUD4 gene relative to other cell lines from the GDSC Cell Line Gene Expression Profiles dataset.
	GeneRIF Biological Term Annotations	biological terms co-occuring with OTUD4 gene in literature-supported statements describing functions of genes from the GeneRIF Biological Term Annotations dataset.
	GeneSigDB Published Gene Signatures	PubMedIDs of publications reporting gene signatures containing OTUD4 from the GeneSigDB Published Gene Signatures dataset.
	GEO Signatures of Differentially Expressed Genes for Diseases	disease perturbations changing expression of OTUD4 gene from the GEO Signatures of Differentially Expressed Genes for Diseases dataset.
	GEO Signatures of Differentially Expressed Genes for Gene Perturbations	gene perturbations changing expression of OTUD4 gene from the GEO Signatures of Differentially Expressed Genes for Gene Perturbations dataset.
	GEO Signatures of Differentially Expressed Genes for Kinase Perturbations	kinase perturbations changing expression of OTUD4 gene from the GEO Signatures of Differentially Expressed Genes for Kinase Perturbations dataset.
	GEO Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of OTUD4 gene from the GEO Signatures of Differentially Expressed Genes for Small Molecules dataset.
	GEO Signatures of Differentially Expressed Genes for Transcription Factor Perturbations	transcription factor perturbations changing expression of OTUD4 gene from the GEO Signatures of Differentially Expressed Genes for Transcription Factor Perturbations dataset.
	GEO Signatures of Differentially Expressed Genes for Viral Infections	virus perturbations changing expression of OTUD4 gene from the GEO Signatures of Differentially Expressed Genes for Viral Infections dataset.