Toggle Main Menu Toggle Search

Open Access padlockePrints

UCHL1-dependent control of hypoxia-inducible factor transcriptional activity during liver fibrosis

Lookup NU author(s): Amy Collins, Rebecca Scott, Dr Caroline WilsonORCiD, Dr Giuseppe Abbate, Steven White, Jeremy French, John Moir, Colin Wilson, Professor Sanjay PandanaboyanaORCiD, John Hammond, Professor Fiona OakleyORCiD, Professor Jelena Mann, Professor Derek Mann

Downloads


Licence

This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2024 The Author(s)Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in most types of chronic liver disease. At the cellular level, liver fibrosis is associated with the activation of hepatic stellate cells (HSCs) which transdifferentiate into a myofibroblast-like phenotype that is contractile, proliferative and profibrogenic. HSC transdifferentiation induces genome-wide changes in gene expression that enable the cell to adopt its profibrogenic functions. We have previously identified that the deubiquitinase ubiquitin C-terminal hydrolase 1 (UCHL1) is highly induced following HSC activation; however, the cellular targets of its deubiquitinating activity are poorly defined. Here, we describe a role for UCHL1 in regulating the levels and activity of hypoxia-inducible factor 1 (HIF1), an oxygen-sensitive transcription factor, during HSC activation and liver fibrosis. HIF1 is elevated during HSC activation and promotes the expression of profibrotic mediator HIF target genes. Increased HIF1α expression correlated with induction of UCHL1 mRNA and protein with HSC activation. Genetic deletion or chemical inhibition of UCHL1 impaired HIF activity through reduction of HIF1α levels. Furthermore, our mechanistic studies have shown that UCHL1 elevates HIF activity through specific cleavage of degradative ubiquitin chains, elevates levels of pro-fibrotic gene expression and increases proliferation rates. As we also show that UCHL1 inhibition blunts fibrogenesis in a pre-clinical 3D human liver slice model of fibrosis, these results demonstrate how small molecule inhibitors of DUBs can exert therapeutic effects through modulation of HIF transcription factors in liver disease. Furthermore, inhibition of HIF activity using UCHL1 inhibitors may represent a therapeutic opportunity with other HIF-related pathologies.


Publication metadata

Author(s): Collins A, Scott R, Wilson CL, Abbate G, Ecclestone GB, Albanese AG, Biddles D, White S, French J, Moir J, Alrawashdeh W, Wilson C, Pandanaboyana S, Hammond JS, Thakkar R, Oakley F, Mann J, Mann DA, Kenneth NS

Publication type: Article

Publication status: Published

Journal: Bioscience Reports

Year: 2024

Volume: 44

Issue: 6

Print publication date: 01/06/2024

Online publication date: 29/05/2024

Acceptance date: 28/05/2024

Date deposited: 01/07/2024

ISSN (print): 0144-8463

ISSN (electronic): 1573-4935

Publisher: Portland Press Ltd

URL: https://doi.org/10.1042/BSR20232147

DOI: 10.1042/BSR20232147

Data Access Statement: All data are available in the manuscript. Raw files for immunoblot analysis are provided in the supplementary information.

PubMed id: 38808772


Altmetrics

Altmetrics provided by Altmetric


Funding

Funder referenceFunder name
C18342/A23390Cancer Research UK CRUK (open competition)
CRUK Discovery Awards
DRCRPG-Nov22/100007
European Region Development Fund
FibroFind ltd.
Intensive Industrial Innovation Programme
MR/K0019494/1
Medical Research Council
MR/R023026/1Medical Research Council (MRC)
Newcastle University Independent Research Establishment Scheme Fellowship
RDG2021.12
North West Cancer Research and Mesothelioma UK Project
North West Cancer Research Development
NWCRMESO 2023.01
WE Harker Foundation

Share