2. Academic Validation
  3. The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis via blocking inactive rhomboid protein 2-dependent pathway

The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis via blocking inactive rhomboid protein 2-dependent pathway

  • Acta Pharm Sin B. 2023 Mar;13(3):1071-1092. doi: 10.1016/j.apsb.2022.12.006.
Minxuan Xu 1 2 3,  Jun Tan 1 2,  Liancai Zhu 3,  Chenxu Ge 1 2 3,  Wei Dong 4,  Xianling Dai 1 3,  Qin Kuang 1 3,  Shaoyu Zhong 1 2,  Lili Lai 1 2,  Chao Yi 1 2,  Qiang Li 1 2,  Deshuai Lou 1 2,  Linfeng Hu 1 2 3,  Xi Liu 1 2,  Gang Kuang 1 2,  Jing Luo 1 2,  Jing Feng 3,  Bochu Wang 3
Affiliations

Affiliations

  • 1 Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China.
  • 2 College of Modern Health Industry, Chongqing University of Education, Chongqing 400067, China.
  • 3 Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China.
  • 4 Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China.
PMID: 36970206 DOI: 10.1016/j.apsb.2022.12.006
Abstract

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated. Inactive rhomboid protein 2 (IRHOM2), a promising target for treatment of inflammation-related diseases, contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanism underlying Irhom2 regulation is still not completely understood. In this work, we identify the Ubiquitin-Specific Protease 13 (USP13) as a critical and novel endogenous blocker of IRHOM2, and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes. Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis, followed by glycometabolic disorder, lipid deposition, increased inflammation, and markedly promotes NASH development. Conversely, transgenic mice with Usp13 overexpression, lentivirus (LV)- or adeno-associated virus (AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent. Mechanistically, in response to metabolic stresses, USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N (UBC13), a ubiquitin E2 conjugating enzyme, and thus prevents its activation of downstream cascade pathway. USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.

Keywords

Hepatosteatosis; Irhom2; Liver inflammation; NAFLD; NASH; Ubc13; Ubiquitination; Usp13.

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