USP4

Last update 08 May 2025

Basic Info

Synonyms

Deubiquitinating enzyme 4, Ubiquitin carboxyl-terminal hydrolase 4, ubiquitin specific peptidase 4

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Introduction

Deubiquitinating enzyme that removes conjugated ubiquitin from target proteins (PubMed:16316627, PubMed:16339847, PubMed:16472766, PubMed:20595234, PubMed:22347420, PubMed:25404403, PubMed:28604766, PubMed:30514904). Deubiquitinates PDPK1 (PubMed:22347420). Deubiquitinates TRIM21 (PubMed:16316627). Deubiquitinates receptor ADORA2A which increases the amount of functional receptor at the cell surface (PubMed:16339847). Deubiquitinates HAS2 (PubMed:28604766). Deubiquitinates RHEB in response to EGF signaling, promoting mTORC1 signaling (PubMed:30514904). May regulate mRNA splicing through deubiquitination of the U4 spliceosomal protein PRPF3 (PubMed:20595234). This may prevent its recognition by the U5 component PRPF8 thereby destabilizing interactions within the U4/U6.U5 snRNP (PubMed:20595234). May also play a role in the regulation of quality control in the ER (PubMed:16339847).

100 Clinical Results associated with USP4

100 Translational Medicine associated with USP4

0 Patents (Medical) associated with USP4

190

Literatures (Medical) associated with USP4

03 Apr 2025·Autophagy

USP4 depletion-driven RAB7A ubiquitylation impairs autophagosome-lysosome fusion and aggravates periodontitis

Article

Author: Liu, Shuxin ; Qian, Yuanyi ; Wang, Huiming ; Li, Haoyu ; Dai, Anna ; Ding, Pei-Hui ; Dong, Xian ; He, Wentao ; Kang, Sen ; Chen, Qianming ; Li, Xiaojun

Periodontitis, a prevalent and chronic inflammatory disease, is intricately linked with macroautophagy/autophagy, which has a dual role in maintaining periodontal homeostasis. Despite its importance, the precise interplay between autophagy and periodontitis pathogenesis remains to be fully elucidated. In this study, our investigation revealed that the ubiquitination of RAB7A, mediated by reduced levels of the deubiquitinating enzyme USP4 (ubiquitin specific peptidase 4), disrupts normal lysosomal trafficking and autophagosome-lysosome fusion, thereby contributing significantly to periodontitis progression. Specifically, through genomic and histological analysis of clinical gingival samples, we observed a decreased RAB7A expression and impaired autophagic activity in periodontitis. This was further substantiated through experimental periodontitis mice, where RAB7A inactivation was shown to directly affect autophagy efficiency and drive periodontitis progression. Next, we explored the function of active RAB7A to promote lysosomal trafficking dynamics and autophagosome-lysosome fusion, which was inhibited by RAB7A ubiquitination in macrophages stimulated by Porphyromonas gingivalis (P. g.), one of the keystone pathogens of periodontitis. Last, by proteomics analysis, we revealed that the ubiquitination of RAB7A was mediated by USP4 and validated that upregulation of USP4 could attenuate periodontitis in vivo. In conclusion, these findings highlight the interaction between USP4 and RAB7A as a promising target for therapeutic intervention in managing periodontal diseases.Abbreviation: 3-MA: 3-methyladenine; Baf A1:bafilomycin A₁; BECN1: beclin 1, autophagy related; CEJ-ABC: cementoenamel junctionto alveolar bone crest; IL1B/IL-1β: interleukin 1 beta; KD:knockdown; LPS: lipopolysaccharide; MOI: multiplicity of infection;OE: overexpression; P.g.: Porphyromonasgingivalis; RILP: Rabinteracting lysosomal protein; ScRNA-seq: single-cell RNA sequencing; SQSTM1/p62: sequestosome 1; S.s.: Streptococcus sanguinis; USP4:ubiquitin specific peptidase 4.

01 Apr 2025·Journal of Affective Disorders

A global overview of shared genetic architecture between smoking behaviors and major depressive disorder in European and East Asian ancestry

Article

Author: Mo, Xiaoxiao ; Chen, Changying ; Shen, Chong ; Xue, Yong ; Wang, Feifan ; Xin, Junyi ; Wang, Chao ; Wu, Dongmei ; Li, Wen ; Han, Xu ; Pu, Qiuyi ; Du, Mulong

BACKGROUNDThe co-occurrence of smoking behaviors and major depressive disorder (MDD) has been widely documented in populations. However, the underlying mechanism of this association remains unclear.METHODSGenome-wide association studies of smoking behaviors and MDD, combined with multi-omics datasets, were used to characterise genetic correlations, identify shared loci and genes, and explore underlying biological mechanisms. Mendelian randomization (MR) analyses were conducted to infer causal relationships between smoking behaviors and MDD. Druggability analyses were performed to identify potential drugs with both antidepressant and smoking cessation effects.RESULTSExtensive overall genetic correlations were found between smoking behaviors and MDD. Furthermore, eighteen local regions showed significant genetic correlations, which could be partly explained by gene co-expression patterns. We identified 24 shared loci and 120 genes, which were enriched in limbic system, GABAergic and dopaminergic neurons, as well as in synaptic pathways. Through integrating with tissue specific information, seven key genes (ANKK1, NEGR1, USP4, TCTA, SORCS5, SPPL3, and USP28) were pinpointed. Notably, druggability analyses supported ANKK1 as a potential drug target for the treatment of MDD and tobacco dependence. MR analyses suggested a bidirectional causal relationship between smoking initiation and MDD. Although findings in East Asian ancestry were limited, the shared locus (chr15:47613403-47,685,504) identified in European ancestry remained significant in East Asian ancestry.CONCLUSIONSOur findings suggest the extensive genetic overlap between smoking behaviors and MDD, support the role of limbic system and synapse involved in shared mechanisms, and implicate for prevention, intervention and treatment.

01 Feb 2025·Molecular Cell

USP4 Auto-Deubiquitylation Promotes Homologous Recombination

Author: Travers, Jonathan ; Wijnhoven, Paul ; Nishi, Ryotaro ; Konietzny, Rebecca ; Kessler, Benedikt M. ; Jackson, Stephen P. ; Blackford, Andrew N.

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