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 p...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.展开更多
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)+4 种基金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).
文摘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.
