The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis <i>via</i> blocking inactive rhomboid protein 2-dependent pathway.

Minxuan XU; Jun Tan; Liancai Zhu; Chenxu GE; Wei Dong; Xianling Dai; Qin Kuang; Shaoyu Zhong; Lili Lai; Chao YI; Qiang LI; Deshuai Lou; Linfeng HU; Xi Liu; Gang Kuang; Jing Luo; Jing Feng; Bochu Wang

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

Author: Minxuan XU ¹ ; Jun TAN ¹ ; Liancai ZHU ² ; Chenxu GE ¹ ; Wei DONG ³ ; Xianling DAI ¹ ; Qin KUANG ¹ ; Shaoyu ZHONG ¹ ; Lili LAI ¹ ; Chao YI ¹ ; Qiang LI ¹ ; Deshuai LOU ¹ ; Linfeng HU ¹ ; Xi LIU ¹ ; Gang KUANG ¹ ; Jing LUO ¹ ; Jing FENG ² ; Bochu WANG ²
Author Information

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. Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400030, China.
3. Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China.
Publication Type:Journal Article
Keywords: Hepatosteatosis; Irhom2; Liver inflammation; NAFLD; NASH; Ubc13; Ubiquitination; Usp13
From: Acta Pharmaceutica Sinica B 2023;13(3):1071-1092
CountryChina
Language:English
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.