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

作     者：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 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

作者机构：Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir RegionSchool of Biological and Chemical EngineeringChongqing University of EducationChongqing 400067China College of Modern Health IndustryChongqing University of EducationChongqing 400067China Key Laboratory of Biorheological Science and Technology(Chongqing University)Ministry of EducationCollege of BioengineeringChongqing UniversityChongqing 400030China Shandong Cancer Hospital and InstituteShandong First Medical University&Shandong Academy of Medical SciencesJinan 250117China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第3期

页      面：1071-1092页

核心收录：

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：supported by National Natural Science Foundation of China(NSFC Grant Nos.81703527 and 82200652) Chongqing Research Program of Basic Research and Frontier Technology(Grant Nos.cstc2017jcyjAX0356,cstc2018jcyjA3686,cstc2018jcyjAX0784,cstc2018jcyjA1472,cstc2018jcyjAX0811,cstc2018jcyjA3533,and KJZD-M201801601,China) School-level Research Program of Chongqing University of Education(Grant Nos.KY201710B and 17GZKP01,China) Advanced Programs of Post-doctor of Chongqing(Grant No.2017LY39,China) Science and Technology Research Program of Chongqing Education Commission of China(Grant Nos.KJQN201901608,KJQN201901615,KJ1601402,and KJZDK202001603) Children's Research Institute of National Center for Schooling Development Programme and Chongqing University of Education(Grant No.CSDP19FSO1108,China) Chongqing Professional Talents Plan for Innovation and Entrepreneurship Demonstration Team(CQCY201903258,China) 

主　　题：Usp13 Irhom2 NASH Hepatosteatosis Ubc13 NAFLD Ubiquitination Liver inflammation 

摘      要：Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis(NASH)have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are *** rhomboid protein 2(IRHOM2),a promising target for treatment of inflammation-related diseases,contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis(NASH)***,the molecular mechanism underlying Irhom2 regulation is still not completely *** 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 ***-specific loss of the Usp13 disrupts liver metabolic homeostasis,followed by glycometabolic disorder,lipid deposition,increased inflammation,and markedly promotes NASH ***,transgenic mice with Usp13 overexpression,lentivirus(LV)-or adeno-associated virus(AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of ***,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 ***13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.