The membrane-associated E3 ubiquitin ligase MARCH3 downregulates the IL-6 receptor and suppresses colitis-associated carcinogenesis  

作　　者：Heng Lin Lu Feng Kai-Sa Cui Lin-Wen Zeng Deng Gao Long-Xiang Zhang Wen-Hua Xu Yu-Hao Sun Hong-Bing Shu Shu Li 

机构地区：[1]Department of Infectious Diseases,Zhongnan Hospital of Wuhan University,Medical Research Institute,Frontier Science Center for Immunology and Metabolism,Research Unit of Innate Immune and Inflammatory Diseases,Chinese Academy of Medical Sciences,Wuhan University,Wuhan,430071,China [2]Wuxi Cancer Institute,Affiliated Hospital of Jiangnan University,Wuxi,214062,Jiangsu,China

出　　处：《Cellular & Molecular Immunology》2021年第12期2648-2659,共12页中国免疫学杂志（英文版）

基　　金：This work was supported by grants from the National Key R&D Program of China(2017YFA0505800);the National Natural Science Foundation of China(31630045,31830024,31900556,and 32070775);the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-071);the National Postdoctoral Program for Innovative Talents(BX20190255);the China Postdoctoral Science Foundation(2019M662706).

摘　　要：The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis(IAC).How this axis is regulated to modulate IAC remains unknown.Here,we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6,as well as another IL-6 subfamily member,Oncostatin M(OSM).MARCH3 is associated with the IL-6 receptorα-chain(IL-6Rα)and its coreceptor gp130.Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rαat K401 and gp130 at K849 following IL-6 stimulation,leading to their translocation to and degradation in lysosomes.MARCH3 deficiency increases IL-6-and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types.MARCH3 deficiency enhances dextran sulfate sodium(DSS)-induced STAT3 activation,increases the expression of inflammatory cytokines,and exacerbates colitis,as well as azoxymethane(AOM)/DSS-induced colitis-associated cancer in mice.In addition,MARCH3 is downregulated in human colorectal cancer tissues and associated with poor survival across different cancer types.Our findings suggest that MARCH3 is a pivotal negative regulator of IL-6-induced STAT3 activation,inflammation,and inflammation-associated carcinogenesis.

关 键 词：MARCH3 IL-6 IL-6Ra colitis-associated carcinogenesis POLYUBIQUITINATION 

分 类 号：R735.3[医药卫生—肿瘤]