细丝蛋白A通过活化Ⅰ型干扰素信号通路抑制H5N6流感病毒复制
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摘要
H5N6 A型流感病毒(influenza A virus, IAV)是严重危害公共卫生安全的新发人兽共患病病原,其复制和致病的科学问题需进一步深入研究.细丝蛋白A(filamin A, FLNA)是一种多功能的肌动蛋白结合蛋白,其可作为细胞信号转导中的支架蛋白,广泛参与细胞内的多种重要生物学过程,但其在流感病毒感染与免疫过程中的作用尚未见报道.前期深度测序分析发现H5N6流感病毒感染细胞后可显著下调FLNA的表达水平,而FLNA过表达能够显著抑制流感病毒在细胞中的复制,并且可以活化Ⅰ型干扰素信号通路.通过siRNA或抑制剂阻断Ⅰ型干扰素下游信号通路之后, FLNA对流感病毒复制的抑制作用消失.以上结果表明, FLNA可以通过活化Ⅰ型干扰素信号通路来抑制H5N6流感病毒在细胞中的复制.本文阐明了FLNA蛋白在流感病毒复制过程中的作用,发现了FLNA参与细胞天然免疫反应的新功能,同时为抗流感病毒药物研发提供了理论依据和研究思路.
H5N6 influenza A virus(IAV) is a newly emerged zoonotic pathogen which seriously poses a threat to public health, and the scientific questions on its replication and pathogenesis need further investigation. Filamin A(filamin A, FLNA) is a multifunctional actin binding protein, which serves as a scaffold in signaling transduction to participate in many cellular processes. However, little is known about its role in the interactions between influenza virus and host immune response. In this study, based on the analysis of deep-sequencing previously, it was found that the expression of FLNA in cells was significantly down-regulated after infection with H5N6 influenza virus, while overexpressed FLNA significantly inhibited the replication of influenza virus in cells and activated the type I interferon signaling pathway. After blocking the downstream type I interferon signaling pathway through siRNA or specific inhibitor, the inhibition effect of FLNA on influenza virus replication disappeared. These results suggest that FLNA inhibits the replication of H5N6 influenza virus in cells through activating the type I interferon signaling pathway. This study for the first time elucidates the role of FLNA protein during influenza virus replication, and reveals the new functions of FLNA in the cellular innate immune response, and provides theoretical basis and novel ideas for the development of anti-viral drugs.
H5N6 influenza A virus(IAV) is a newly emerged zoonotic pathogen which seriously poses a threat to public health, and the scientific questions on its replication and pathogenesis need further investigation. Filamin A(filamin A, FLNA) is a multifunctional actin binding protein, which serves as a scaffold in signaling transduction to participate in many cellular processes. However, little is known about its role in the interactions between influenza virus and host immune response. In this study, based on the analysis of deep-sequencing previously, it was found that the expression of FLNA in cells was significantly down-regulated after infection with H5N6 influenza virus, while overexpressed FLNA significantly inhibited the replication of influenza virus in cells and activated the type I interferon signaling pathway. After blocking the downstream type I interferon signaling pathway through siRNA or specific inhibitor, the inhibition effect of FLNA on influenza virus replication disappeared. These results suggest that FLNA inhibits the replication of H5N6 influenza virus in cells through activating the type I interferon signaling pathway. This study for the first time elucidates the role of FLNA protein during influenza virus replication, and reveals the new functions of FLNA in the cellular innate immune response, and provides theoretical basis and novel ideas for the development of anti-viral drugs.
引文
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19 Li Y,Sun Y,Sun F,et al.Mechanisms and effects on HBV replication of the interaction between HBV core protein and cellular filamin B.Virol Sin,2018,33:162-172
2 Chen H,Deng G,Li Z,et al.The evolution of H5N1 influenza viruses in ducks in southern China.Proc Natl Acad Sci USA,2004,101:10452-10457
3 Li Z,Jiang Y,Jiao P,et al.The NS1 gene contributes to the virulence of H5N1 avian influenza viruses.J Virol,2006,80:11115-11123
4 Shen H,Wu B,Chen Y,et al.Influenza A(H5N6)virus reassortant,Southern China,2014.Emerg Infect Dis,2015,21:1261-1262
5 Li X,Fu Y,Yang J,et al.Genetic and biological characterization of two novel reassortant H5N6 swine influenza viruses in mice and chickens.Infec Genets Evol,2015,36:462-466
6 Jiang H,Wu P,Uyeki T M,et al.Preliminary epidemiologic assessment of human infections with highly pathogenic avian influenza A(H5N6)virus,China.Clin Infect Dis,2017,65:383-388
7 Nakamura F,Osborn T M,Hartemink C A,et al.Structural basis of filamin A functions.J Cell Biol,2007,179:1011-1025
8 Feng Y,Walsh C A.The many faces of filamin:a versatile molecular scaffold for cell motility and signalling.Nat Cell Biol,2004,6:1034-1038
9 Savinko T,Guenther C,Uotila L M,et al.Filamin A is required for optimal T cell integrin-mediated force transmission,flow adhesion,and T cell trafficking.J Immunol,2018,200:3109-3116
10 Cooper J A,Liu L,Woodruff E A,et al.Filamin A protein interacts with human immunodeficiency virus type 1 Gag protein and contributes to productive particle assembly.J Biol Chem,2011,286:28498-28510
11 Dotson D,Woodruff E A,Villalta F,et al.Filamin A is involved in HIV-1 vpu-mediated evasion of host restriction by modulating tetherin expression.J Biol Chem,2016,291:4236-4246
12 Wang J,Zhao S,Wei Y,et al.Cytoskeletal filamin A differentially modulates RNA polymerase III gene transcription in transformed cell lines.JBiol Chem,2016,291:25239-25246
13 Nakagawa R,Yoshida H,Asakawa M,et al.Pyridone 6,a pan-JAK inhibitor,ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17.J Immunol,2011,187:4611-4620
14 Bowie A G,Unterholzner L.Viral evasion and subversion of pattern-recognition receptor signalling.Nat Rev Immunol,2008,8:911-922
15 Sadler A J,Williams B R G.Interferon-inducible antiviral effectors.Nat Rev Immunol,2008,8:559-568
16 Kisseleva T,Bhattacharya S,Braunstein J,et al.Signaling through the JAK/STAT pathway,recent advances and future challenges.Gene,2002,285:1-24
17 Liu Y,Belkina N V,Shaw S.HIV infection of T cells:actin-in and actin-out.Sci Signal,2009,2:pe23
18 Jeon Y J,Choi J S,Lee J Y,et al.Filamin B serves as a molecular scaffold for type I interferon-induced c-Jun NH2-terminal kinase signaling pathway.MBoC,2008,19:5116-5130
19 Li Y,Sun Y,Sun F,et al.Mechanisms and effects on HBV replication of the interaction between HBV core protein and cellular filamin B.Virol Sin,2018,33:162-172