P21-activated kinase 1 (PAK1)-mediated cytoskeleton rearrangement promotes SARS-CoV-2 entry and ACE2 autophagic degradation  

作　　者：Ming Liu Bingtai Lu Yue Li Shuofeng Yuan Zhen Zhuang Guangyu Li Dong Wang Liuheyi Ma Jianheng Zhu Jinglu Zhao Chris Chung-Sing Chan Vincent Kwok-Man Poon Kenn Ka-Heng Chik Zhiyao Zhao Huifang Xian Jingxian Zhao Jincun Zhao Jasper Fuk-Woo Chan Yuxia Zhang 

机构地区：[1]Guangzhou Institute of Pediatrics,Guangzhou Women and Children's Medical Centre,State Key Laboratory of Respiratory Diseases,Guangzhou Medical University,510623 Guangzhou,Guangdong,China [2]Medical Research Institute,Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences),Southern Medical University,Guangdong,China [3]State Key Laboratory of Emerging Infectious Diseases,Carol Yu Centre for Infection,Department of Microbiology,School of Clinical Medicine,Li Ka Shing Faculty of Medine,The University of Hong Kong,Pokfulam,Hong Kong,China [4]Department of Clinical Microbiology and Infection Control,The University of Hong Kong Shenzhen Hospital,Shenzhen,Guangdong,China [5]Centre for Virology,Vaccinology and Therapeutics,Hong Kong Science and Technology Park,Hong Kong,China [6]State Key Laboratory of Respiratory Disease,National Clinical Research Center for Respiratory Disease,Guangzhou Institute of Respiratory Health,the First Affliated Hospital of Guangzhou Medical University,Guangzhou,China [7]The Third Afliated Hospital of Zhengzhou University,450052 Zhengzhou,China [8]Guangzhou Laboratory,Guangzhou,Guangdong Province,China [9]Chongqing International Institute for Immunology,Chongqing,China

出　　处：《Signal Transduction and Targeted Therapy》2023年第11期5353-5367,共15页信号转导与靶向治疗（英文）

基　　金：the National Natural Science Foundation of China(NSFC;Nos.#82000007 toM.L.,#82001676 and#91842304 to B.T.L,#82125015 to Y.X.Z.#82272337 to J.F.W.C.);the GWCMC Postdoc Fund(Nos.#5001-3001061 to M.L.,#5001-3001060 to B.T.L.);Chongqing International Institute for Immunology(No.#2021YJC02 to Y.X.Z.);the Guangzhou Basic and Applied Basic Research Fund for Young Ph.D.scientists(No.#202102020194 to M.L.);Zhongnanshan Medical Foundation of Guangdong Province(No.#ZNSA-2020013 to J.C.Z.and Y.X.Z.);the General Research Fund(No.#17122322 to J.F.W.C.);Sanming Project of Medicine in Shenzhen,China(No.#SZSM201911014 to J.F.W.C.);the High Level-Hospital Program,Health Commission of Guangdong Province,China(to J.F.W.C.);and Emergency Collaborative Project(No.#EKPG22-01)of Guangzhou Laboratory(to J.F.W.C.).

摘　　要：Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of coronavirus disease 2019(COVID-19),has had a significant impact on healthcare systems and economies worldwide.The continuous emergence of new viral strains presents a major challenge in the development of effective antiviral agents.Strategies that possess broad-spectrum antiviral activities are desirable to control SARS-CoV-2 infection.ACE2,an angiotensin-containing enzyme that prevents the overactivation of the renin angiotensin system,is the receptor for SARS-CoV-2.ACE2 interacts with the spike protein and facilitates viral attachment and entry into host cells.Yet,SARS-CoV-2 infection also promotes ACE2 degradation.Whether restoring ACE2 surface expression has an impact on SARS-CoV-2 infection is yet to be determined.Here,we show that the ACE2-spike complex is endocytosed and degraded via autophagy in a manner that depends on clathrin-mediated endocytosis and PAK1-mediated cytoskeleton rearrangement.In contrast,free cellular spike protein is selectively cleaved into S1 and s2 subunits in a lysosomal-dependent manner.Importantly,we show that the pan-PAK inhibitor FRAX-486 restores ACE2 surface expression and suppresses infection by different SARS-CoV-2 strains.FRAX-486-treated Syrian hamsters exhibit significantly decreased lung viral load and alleviated pulmonary inflammation compared with untreated hamsters.In summary,our findings have identified novel pathways regulating viral entry,as well as therapeutic targets and candidate compounds for controlling the emerging strains of SARS-CoV-2 infection.

关 键 词：ACE2 inflammation REARRANGEMENT 

分 类 号：R563.1[医药卫生—呼吸系统]