Novel insights into stress-induced susceptibility to influenza:corticosterone impacts interferon-βresponses by Mfn2-mediated ubiquitin degradation of MAVS  

作　　者：Zhuo Luo Li-Fang Liu Ying-Nan Jiang Lu-Ping Tang Wen Li Shu-Hua Ouyang Long-Fang Tu Yan-Ping Wu Hai-Biao Gong Chang-Yu Yan Shan Jiang Yu-Hui Lu Tongzheng Liu Zhenyou Jiang Hiroshi Kurihara Yang Yu Xin-Sheng Yao Yi-Fang Li Rong-Rong He 

机构地区：[1]Guangdong Engineering Research Center of Chinese Medicine&Disease Susceptibility,Jinan University,Guangzhou 510632,China [2]International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education(MOE),College of Pharmacy,Jinan University,Guangzhou 510632,China [3]Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research,College of Pharmacy,Jinan University,Guangzhou 510632,China [4]School of Traditional Chinese Materia Medica,Shenyang Pharmaceutical University,Shenyang 110016,China [5]Institute of Tumor Pharmacology,College of Pharmacy,Jinan University,Guangzhou 510632,China [6]Department of Microbiology and Immunology,Basic Medicine College,Jinan University,GuangZhou 510632,China

出　　处：《Signal Transduction and Targeted Therapy》2020年第1期782-793,共12页信号转导与靶向治疗（英文）

基　　金：supported,in part,by Natural Science Foundation of China(grant numbers 81622050,81573675,U1801284,81673709,81873209);National Key Research and Development Program of China(grant number 2017YFC1700404);the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(grant number 2017BT01Y036)and GDUPS(2019);the Guangdong Science and Technology Foundation for Distinguished Young Scholars(grant number 2017A030306004);the Youth Top-notch Talent Support Program of Guangdong Province(2016TQ03R586);the Program of Hong Kong Scholar(XJ2016017);the Science and Technology Program of Guangzhou(grant number 201903010062).

摘　　要：Although stress has been known to increase the susceptibility of pathogen infection,the underlying mechanism remains elusive.In this study,we reported that restraint stress dramatically enhanced the morbidity and mortality of mice infected with the influenza virus(H1N1)and obviously aggravated lung inflammation.Corticosterone(CORT),a main type of glucocorticoids in rodents,was secreted in the plasma of stressed mice.We further found that this stress hormone significantly boosted virus replication by restricting mitochondrial antiviral signaling(MAVS)protein-transduced IFN-βproduction without affecting its mRNA level,while the deficiency of MAVS abrogated stress/CORT-induced viral susceptibility in mice.Mechanistically,the effect of CORT was mediated by proteasome-dependent degradation of MAVS,thereby resulting in the impediment of MAVS-transduced IFN-βgeneration in vivo and in vitro.Furthermore,RNA-seq assay results indicated the involvement of Mitofusin 2(Mfn2)in this process.Gain-and loss-offunction experiments indicated that Mfn2 interacted with MAVS and recruited E3 ligase SYVN1 to promote the polyubiquitination of MAVS.Co-immunoprecipitation experiments clarified an interaction between any two regions of Mfn2(HR1),MAVS(C-terminal/TM)and SYVN1(TM).Collectively,our findings define the Mfn2-SYVN1 axis as a new signaling cascade for proteasome-dependent degradation of MAVS and a‘fine tuning’of antiviral innate immunity in response to influenza infection under stress.

关 键 词：INFLUENZA UBIQUITIN MAVS 

分 类 号：R96[医药卫生—药理学]