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Last update 08 May 2025

USP46

Last update 08 May 2025

Basic Info

Synonyms

Deubiquitinating enzyme 46, FLJ12552, Ubiquitin carboxyl-terminal hydrolase 46

+ [4]

Introduction

Deubiquitinating enzyme that plays a role in behavior, possibly by regulating GABA action. May act by mediating the deubiquitination of GAD1/GAD67 (By similarity). Has almost no deubiquitinating activity by itself and requires the interaction with WDR48 to have a high activity (PubMed:19075014, PubMed:26388029). Not involved in deubiquitination of monoubiquitinated FANCD2 (PubMed:19075014).

Drugs associated with USP46

CN116855497

Patent Mining

Target

USP46

Mechanism-

Active Org.

Jinan University

Originator Org.

Jinan University

Active Indication

Neoplasms [+1]

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with USP46

100 Translational Medicine associated with USP46

0 Patents (Medical) associated with USP46

Literatures (Medical) associated with USP46

01 Apr 2025·Experimental Neurology

Heliox alleviates ischemia-reperfusion-induced damage to neuronal cells by repressing the USP46-SNX5 Axis-triggered ferroptosis

Article

Author: Wang, Zhanxiang ; Zhou, Liying ; Yang, Hualing ; Xiong, Wei ; Yu, Shuai

BACKGROUNDCerebral ischemia-reperfusion (I/R) causes brain cell dysfunction and death. Heliox treatment shows therapeutic benefits in treating certain respiratory conditions. Here, we explore the mechanism by which heliox alleviates ferroptosis of neuronal cells injured by I/R treatment.METHODOGD/R-treated SH-SY5Y cells were used and screened for USPs whose expression is induced by OGD/R but suppressed by heliox treatment. Mass spectrometry was conducted to identify proteins that interact with USP46. The impact of SNX5 deficiency on the ferroptosis of USP46-overexpressing neuronal cells following sequential OGD/R and heliox treatment was also explored. Finally, the effect of USP46 overexpression on brain cell ferroptosis in a cerebral I/R rat model was explored.RESULTSDeubiquitinase USP46 is targeted by heliox treatment in neuronal cells. USP46 expression is stimulated by I/R, and its overexpression enhances ferroptosis in I/R-treated neuronal cells. USP46 interacts with and deubiquitinates SNX5, a ferroptosis promoter, thereby increasing its stability. The knockdown of SNX5 abolishes the ferroptosis-promoting effect of USP46 in I/R-treated neuronal cells. Excessive USP46 attenuates the protective effect of heliox treatment on I/R-triggered cerebral damage in a rat model.CONCLUSIONThese observations highlight the ferroptosis-promoting function of the USP46-SNX5 axis in I/R-treated neuronal cells.

01 Apr 2025·Acta Biochimica et Biophysica Sinica

Integrated quantitative proteomics and phosphoproteomics analysis reveals USP46-POU4F1-HPSE signaling axis in the pathogenesis of Hirschsprung disease

Article

Author: Chen, Jiawei ; Xu, Qiongqian ; Hou, Peimin ; Zhang, Xintao ; Sun, Fengyin ; Chen, Luqiu ; Li, Aiwu ; Li, Guowei

Hirschsprung's disease (HSCR) is a congenital disorder characterized by the absence of enteric ganglion cells in the distal colon, resulting in functional intestinal obstruction. While genetic mutations and microenvironmental imbalances have been implicated in HSCR, the underlying molecular mechanisms are not fully understood. This study uses integrated quantitative proteomics and phosphoproteomics analyses to characterize the differential protein profiles and phosphorylation modifications associated with HSCR. These findings reveal significant dysregulation of the extracellular matrix (ECM) remodelling pathway, suggesting its potential involvement in HSCR pathogenesis. Notably, the deubiquitinating enzyme USP46 is found to be significantly reduced in the aganglionic segments of HSCR patients. Through IP-MS, GST pull-down, and co-immunoprecipitation assays, it is demonstrated that USP46 interacts with the transcription factor POU4F1. Mechanistically, USP46 stabilizes POU4F1 via deubiquitination, increasing its binding to the heparanase (HPSE) promoter and increasing HPSE expression, which in turn promotes ECM remodelling and neural cell migration. The role of the USP46-POU4F1-HPSE signaling axis in HSCR pathogenesis is confirmed via chromatin immunoprecipitation-qPCR, luciferase reporter assays, and transwell migration assays. This study elucidates a novel regulatory mechanism linking USP46-mediated protein stabilization to ECM dynamics and neural cell migration, offering new insights into HSCR pathogenesis and potential therapeutic targets.

01 Jan 2025·FEBS Open Bio

Proximity‐dependent biotinylation reveals an interaction between ubiquitin‐specific peptidase 46 and centrosome‐related proteins

Article

Author: Nakagawa, Reiko ; Mizuno, Seiya ; Suzuki, Hayate ; Okiyoneda, Tsukasa ; Ishigaki, Kiyohiro ; Yoshioka, Kazuma ; Murata, Kazuya ; Nguyen, Chi Lieu Kim ; Ebihara, Shizufumi

Protein ubiquitination extensively modulates protein functions and controls various biological processes, such as protein degradation, signal transduction, transcription, and DNA repair. Ubiquitination is a reversible post‐translational modification, and deubiquitinating enzymes cleave ubiquitin from proteins. Ubiquitin‐specific peptidase 46 (USP46), a deubiquitinase, is highly expressed in the brain and regulates neural functions. Deleting lysine 92 (ΔK92) in USP46 reduces murine depression‐like behavior in the tail suspension test. However, the molecular basis for USP46's role in regulating neural function has not yet been fully understood. Here we employed a proximity‐dependent biotinylation approach to characterize the USP46 protein interaction partners. Using homology‐independent targeted integration (HITI), a genome editing technique, we established knockin cell lines that stably express USP46 wildtype‐ or ΔK92‐biotin ligase fusion protein. We identified 286 candidate interaction partners, including well‐known binding partners of USP46. Although there were no obvious differences in the interactome of USP46 between wildtype and ΔK92, a gene ontology analysis revealed that centrosome‐related proteins were significantly enriched in the proximal proteins of USP46. Several centrosome‐related proteins were bound to USP46 in Neuro2a cells, but their protein expression levels were not affected in the brains of USP46‐deficient mice. These results uncover a potential relationship between USP46 and centrosome regulation independently of protein stabilization.

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USP46

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