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Last update 08 May 2025

UCHL5

Last update 08 May 2025

Basic Info

Synonyms

CGI-70, INO80 complex subunit R, INO80R

+ [8]

Introduction

Protease that specifically cleaves 'Lys-48'-linked polyubiquitin chains. Deubiquitinating enzyme associated with the 19S regulatory subunit of the 26S proteasome. Putative regulatory component of the INO80 complex; however is inactive in the INO80 complex and is activated by a transient interaction of the INO80 complex with the proteasome via ADRM1.

Drugs associated with UCHL5

b-AP15

Target

UCHL5 x USP14

Mechanism

UCHL5 inhibitors [+1]

Active Org.

National Taiwan University Hospital

Originator Org.

Karolinska Institutet

Active Indication

Renal Cell Carcinoma

Inactive Indication

Adult Acute Myeloblastic Leukemia

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

VLX-600

Target

UCHL5 x USP14

Mechanism

UCHL5 inhibitors [+1]

Active Org.-

Originator Org.

Karolinska Institutet

Active Indication-

Inactive Indication

Refractory Cancer [+1]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

VLX-1570

Target

UCHL5 x USP14

Mechanism

UCHL5 inhibitors [+1]

Active Org.-

Originator Org.

Vivolux AB

Active Indication-

Inactive Indication

Multiple Myeloma [+1]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with UCHL5

NCT02372240

/ TerminatedPhase 1/2

VLX1570 and Low-Dose Dexamethasone in Relapsed or Relapsed and Refractory Multiple Myeloma: A Clinical and Correlative Phase 1/2 Study

This is a phase 1/2 single arm study to determine the safety and efficacy of VLX1570 IV infusion administered with low dose dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma.

Start Date08 Apr 2015

Sponsor / Collaborator

Vivolux AB

[+1]

NCT02222363

/ TerminatedPhase 1

A Phase I Study of the Safety and Tolerability of VLX600, an Iron Chelator, in Patients With Refractory Advanced Solid Tumors

The purpose of this study is to evaluate the safety and tolerability of the investigational drug VLX600 in patients with refractory advanced solid tumors.

Start Date18 Feb 2015

Sponsor / Collaborator

Vivolux AB

[+1]

100 Clinical Results associated with UCHL5

100 Translational Medicine associated with UCHL5

0 Patents (Medical) associated with UCHL5

251

Literatures (Medical) associated with UCHL5

15 Feb 2025·Biology Open

Impairment of proteasome-associated deubiquitinating enzyme Uchl5/UBH-4 affects autophagy

Article

Author: Jha, Sweta ; Pispa, Johanna ; Holmberg, Carina I.

ABSTRACTThe autophagy–lysosomal pathway (ALP) and the ubiquitin–proteasome system (UPS) are the two major intracellular proteolytic systems that mediate protein turnover in eukaryotes. Although a crosstalk exists between these two systems, it is still unclear how UPS and ALP interact in vivo. Here, we investigated how impaired function of the proteasome-associated deubiquitinating enzyme (DUB) Uchl5/UBH-4 affects autophagy in human cells and in a multicellular organism. We show that downregulation of Uchl5 by siRNA reduces autophagy by partially blocking the fusion of autophagosomes with the lysosomes in HeLa cells, which is similar to a previously reported role of the proteasome-associated DUB Usp14 on autophagy. However, exposure of Caenorhabditis elegans to ubh-4 or usp-14 RNAi, or to their pharmacological inhibitors, results in diverse effects on numbers of autophagosomes and autolysosomes, without blocking the lysosomal fusion, in the intestine, hypodermal seam cells and the pharynx. Our results reveal that impairment of Uchl5/UBH-4 and Usp14 affects autophagy in a tissue context manner. A deeper insight into the interplay between UPS and ALP in various tissues in vivo has the potential to promote development of therapeutic approaches for disorders associated with proteostasis dysfunction.

01 Dec 2024·Biochemical and Biophysical Research Communications

Deubiquitinase inhibitor bAP-15 suppresses renal epithelial to mesenchymal transition via inhibition of p300 stability

Article

Author: Yoon, Ho-Geun ; Lee, Sun-Ho ; Kim, Hyunseung ; Kwon, Jae-Hwan ; Yoo, Jung-Yoon ; Kim, Hyunsik ; Byun, Seunghee ; Park, Soo-Yeon

Renal fibrosis is an irreversible disease that is common in patients with chronic kidney disease. Elevated levels of the histone acetyltransferase p300 have been reported in various fibrotic diseases, including renal fibrosis, suggesting that p300 may be a promising therapeutic target. To investigate the specific deubiquitinase (DUB) involved in the regulation of p300 protein stability in renal epithelial cells, we tested 13 DUB inhibitors using a kidney tubular epithelial cell line. We found that the p300-specific DUB inhibitor, bAP-15 reduces p300 protein stability by targeting ubiquitin-specific protease 14 (USP14) and ubiquitin C-terminal hydrolase L5 (UCHL5). The mRNA levels of USP14 and UCHL5 were increased in patients with chronic kidney disease, and increased protein levels of USP14 and UCHL5 during fibrosis progression were validated using a mouse renal fibrosis model. Both USP14 and UCHL5 interacted with p300 in kidney tubular epithelial cells, with increased binding affinity in response to TGF-β. Moreover, bAP-15-induced p300 degradation inhibited epithelial-to-mesenchymal transition and reduced the expression of pro-fibrotic target genes. Our findings demonstrate an anti-fibrotic effect of bAP-15 through the regulation of p300 stability and suggest that bAP-15 may be a potential therapeutic agent for renal fibrosis.

01 Oct 2024·Oral Diseases

USP14 promotes the cancer stem‐like cell properties of OSCC via promoting SOX2 deubiquitination

Article

Author: Tang, Wei ; Liu, Chang ; Zhou, Shijie

AbstractObjectiveUSP14 (Ubiquitin‐specific‐processing protease 14) is a deubiquitinating enzyme with oncogenic effects in oral squamous cell carcinoma (OSCC). This study aims to identify new substrates of USP14 and elucidate their role in modulating cancer stem‐like cells (CSCs) in OSCC.Materials and MethodsBioinformatics prediction and docking were performed using UbiBrowser 2.0 and HDOCK, respectively. OSCC cell lines and patient‐derived cells were used for experimental validation, employing co‐immunoprecipitation, cycloheximide chase assays, and tumor sphere formation to evaluate the effects of USP14 on SOX2 stability, ubiquitination, and CSC phenotypes.ResultsUSP14 upregulation was associated with worse overall survival and progression‐free interval in OSCC. USP14 interacted with SOX2 with its ubiquitin carboxyl‐terminal hydrolase domain. USP14 knockdown impaired SOX2 stability by increasing its polyubiquitination. Ectopic overexpression of wild‐type USP14, but not the hydrolase‐deficient‐mutant USP14C114A, enhanced SOX2 stability by reducing polyubiquitination. USP14 knockdown suppressed OSCC cell proliferation, colony formation, and tumor sphere formation in vitro and tumor growth in vivo. However, the reduction of CSC markers following USP14 knockdown was mitigated by overexpressing SOX2. These findings were verified in OSCC patient‐derived CSC cells.ConclusionThis study revealed a USP14‐SOX2 axis regulating the CSC properties of OSCC.

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UCHL5

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