Deubiquitinase JOSD2 alleviates colitis by inhibiting inflammation via deubiquitination of IMPDH2 in macrophages  

作　　者：Xin Liu Yi Fang Mincong Huang Shiliang Tu Boan Zheng Hang Yuan Peng Yu Mengyao Lan Wu Luo Yongqiang Zhou Guorong Chen Zhe Shen Yi Wang Guang Liang 

机构地区：[1]Department of Pharmacy and Institute of Inflammation,Zhejiang Provincial People’s Hospital,Affiliated People’s Hospital of Hangzhou Medical College,Hangzhou 310014,China [2]Department of Colorectal Surgery,Zhejiang Provincial People’s Hospital,Affiliated People’s Hospital of Hangzhou Medical College,Hangzhou 310014,China [3]Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325035,China [4]Zhejiang TCM Key Laboratory of Pharmacology and Translational Research of Natural Products,School of Pharmaceutical Sciences,Hangzhou Medical College,Hangzhou 311399,China [5]Department of Radiation and Medical Oncology,the First Affiliated Hospital of Wenzhou Medical University,Wenzhou 325035,China [6]Department of Pathology,the Affiliated Quzhou Hospital of Wenzhou Medical University,Quzhou 32400,China [7]The Department of Gastroenterology,the First Affiliated Hospital,School of Medicine,Zhejiang University,Hangzhou 310003,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第2期1039-1055,共17页药学学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(82300589 to Xin Liu,82004042 to Mincong Huang,and 82370244 to Yi Wang);the Zhejiang Provincial Key Scientific Project(2021C03041 to Guang Liang,China).

摘　　要：Inflammatory bowel disease(IBD)is a chronic inflammatory disorder of the gastrointestinal tract,which increases the incidence of colorectal cancer(CRC).In the pathophysiology of IBD,ubiquitination/deubiquitination plays a critical regulatory function.Josephin domain containing 2(JOSD2),a deubiquitinating enzyme,controls cell proliferation and carcinogenesis.However,its role in IBD remains unknown.Colitis mice model developed by dextran sodium sulfate(DSS)or colon tissues from individuals with ulcerative colitis and Crohn's disease showed a significant upregulation of JOSD2 expression in the macrophages.JOSD2 deficiency exacerbated the phenotypes of DSS-induced colitis by enhancing colon inflammation.DSS-challenged mice with myeloid-specific JOSD2 deletion developed severe colitis after bone marrow transplantation.Mechanistically,JOSD2 binds to the C-terminal of inosine-5′-monophosphate dehydrogenase 2(IMPDH2)and preferentially cleaves K63-linked polyubiquitin chains at the K134 site,suppressing IMPDH2 activity and preventing activation of nuclear factor kappa B(NF-κB)and inflammation in macrophages.It was also shown that JOSD2 knockout significantly exacerbated increased azoxymethane(AOM)/DSS-induced CRC,and AAV6-mediated JOSD2 overexpression in macrophages prevented the development of colitis in mice.These outcomes reveal a novel role for JOSD2 in colitis through deubiquitinating IMPDH2,suggesting that targeting JOSD2 is a potential strategy for treating IBD.

关 键 词：COLITIS Deubiquitinase JOSD2 IMPDH2 INFLAMMATION Inflammatory bowel disease MACROPHAGE Nuclear factor kappa B 

分 类 号：R574.62[医药卫生—消化系统]