Tauroursodeoxycholic acid(TUDCA) inhibits influenza A viral infection by disrupting viral proton channel M2
|
摘要
Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza(HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid(TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity,an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.
Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza(HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid(TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity,an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.
Influenza is a persistent threat to human health and there is a continuing requirement for updating antiinfluenza strategies. Initiated by observations of different endoplasmic reticulum(ER) responses of host to seasonal H1N1 and highly pathogenic avian influenza(HPAI) A H5N1 infections, we identified an alternative antiviral role of tauroursodeoxycholic acid(TUDCA), a clinically available ER stress inhibitor, both in vitro and in vivo. Rather than modulating ER stress in host cells, TUDCA abolished the proton conductivity of viral M2 by disrupting its oligomeric states, which induces inefficient viral infection. We also showed that M2 penetrated cells, whose intracellular uptake depended on its proton channel activity,an effect observed in both TUDCA and M2 inhibitor amantadine. The identification and application of TUDCA as an inhibitor of M2 proton channel will expand our understanding of IAV biology and complement current anti-IAV arsenals.
引文
[1] Taubenberger JK, Kash JC. Influenza virus evolution, host adaptation, and pandemic formation. Cell Host Microbe 2010;7:440–51.
[2] Herfst S, Schrauwen EJ, Linster M, et al. Airborne transmission of influenza a/h5n1 virus between ferrets. Science 2012;336:1534–41.
[3] de Jong MD, Simmons CP, Thanh TT, et al. Fatal outcome of human influenza a(h5n1)is associated with high viral load and hypercytokinemia. Nat Med2006;12:1203–7.
[4] Edinger TO, Pohl MO, Stertz S. Entry of influenza a virus:host factors and antiviral targets. J General Virol 2014;95:263–77.
[5] Skehel JJ, Wiley DC. Receptor binding and membrane fusion in virus entry:the influenza hemagglutinin. Annu Rev Biochem 2000;69:531–69.
[6] Stauffer S, Feng Y, Nebioglu F, et al. Stepwise priming by acidic ph and a high K+concentration is required for efficient uncoating of influenza a virus cores after penetration. J Virol 2014;88:13029–46.
[7] Shulman NS, Kassaye SG, Winters MA, et al. More on the treatment-tropism relationship:the impact of prior antiretroviral treatment on hiv coreceptor tropism among subjects entering aids clinical trials group 175. J Infectious Dis2007;196:328–9.
[8] Sakaguchi T, Tu Q, Pinto LH, et al. The active oligomeric state of the minimalistic influenza virus m2 ion channel is a tetramer. Proc Natl Acad Sci USA 1997;94:5000–5.
[9] Schnell JR, Chou JJ. Structure and mechanism of the m2 proton channel of influenza a virus. Nature 2008;451:591–5.
[10] Kawano K, Yano Y, Matsuzaki K. A dimer is the minimal proton-conducting unit of the influenza a virus m2 channel. J Mol Biol 2014;426:2679–91.
[11] Tobler K, Kelly ML, Pinto LH, et al. Effect of cytoplasmic tail truncations on the activity of the m(2)ion channel of influenza a virus. J Virol 1999;73:9695–701.
[12] Kochendoerfer GG, Salom D, Lear JD, et al. Total chemical synthesis of the integral membrane protein influenza a virus m2:role of its c-terminal domain in tetramer assembly. Biochemistry 1999;38:11905–13.
[13] Holsinger LJ, Nichani D, Pinto LH, et al. Influenza a virus m2 ion channel protein:a structure-function analysis. J Virol 1994;68:1551–63.
[14] Ekanayake EV, Fu R, Cross TA. Structural influences:cholesterol, drug, and proton binding to full-length influenza a m2 protein. Biophys J2016;110:1391–9.
[15] Kim SS, Upshur MA, Saotome K, et al. Cholesterol-dependent conformational exchange of the c-terminal domain of the influenza a m2 protein.Biochemistry 2015;54:7157–67.
[16] Nguyen PA, Soto CS, Polishchuk A, et al. Ph-induced conformational change of the influenza m2 protein c-terminal domain. Biochemistry 2008;47:9934–6.
[17] Georgieva ER, Borbat PP, Norman HD, et al. Mechanism of influenza a m2transmembrane domain assembly in lipid membranes. Sci Rep 2015;5:11757.
[18] de Aguiar Vallim TQ, Tarling EJ, Edwards PA. Pleiotropic roles of bile acids in metabolism. Cell Metab 2013;17:657–69.
[19] Boatright JH, Nicker son JM, Moring AG, et al. Bile acids in treatment of ocular disease. J Ocular Biol Dis Informatics 2009;2:149–59.
[20] Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce er stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science2006;313:1137–40.
[21] Yan H, Peng B, Liu Y, et al. Viral entry of hepatitis b and d viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide. J Virol 2014;88:3273–84.
[22] Hassan IH, Zhang MS, Powers LS, et al. Influenza a viral replication is blocked by inhibition of the inositol-requiring enzyme 1(ire1)stress pathway. J Biol Chem 2012;287:4679–89.
[23] Hrincius ER, Liedmann S, Finkelstein D, et al. Acute lung injury results from innate sensing of viruses by an er stress pathway. Cell Rep 2015;11:1591–603.
[24] Matute-Bello G, Downey G, Moore BB, et al. An official american thoracic society workshop report:features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol 2011;44:725–38.
[25] Sulli C, Banik SS, Schilling J, et al. Detection of proton movement directly across viral membranes to identify novel influenza virus m2 inhibitors. J Virol2013;87:10679–86.
[26] Banerjee I, Yamauchi Y, Helenius A, et al. High-content analysis of sequential events during the early phase of influenza a virus infection. PLoS One 2013;8:e68450.
[27] Desplanques AS, Nauwynck HJ, Vercauteren D, et al. Plasma membrane cholesterol is required for efficient pseudorabies virus entry. Virology2008;376:339–45.
[28] Sun X, Whittaker GR. Role for influenza virus envelope cholesterol in virus entry and infection. J Virol 2003;77:12543–51.
[29] Fujioka Y, Tsuda M, Nanbo A, et al. A Ca2+dependent signalling circuit regulates influenza a virus internalization and infection. Nat Commun 2013;4:2763.
[30] Bechara C, Sagan S. Cell-penetrating peptides:20 years later, where do we stand? FEBS Lett 2013;587:1693–702.
[31] Guo Z, Peng H, Kang J, et al. Cell-penetrating peptides:possible transduction mechanisms and therapeutic applications. Biomed Rep 2016;4:528–34.
[32] Milletti F. Cell-penetrating peptides:classes, origin, and current landscape.Drug Discovery Today 2012;17:850–60.
[33] Claridge JK, Aittoniemi J, Cooper DM, et al. Isotropic bicelles stabilize the juxtamembrane region of the influenza m2 protein for solution nmr studies.Biochemistry 2013;52:8420–9.
[34] Rossman JS, Jing X, Leser GP, et al. Influenza virus m2 protein mediates escrtindependent membrane scission. Cell 2010;142:902–13.
[35] Shen H, Pirruccello M, De Camilli P. Snapshot:membrane curvature sensors and generators. Cell 2012;150:1300.
[36] Faustino C, Serafim C, Rijo P, et al. Bile acids and bile acid derivatives:use in drug delivery systems and as therapeutic agents. Expert Opin Drug Delivery2016;13:1133–48.
[37] Thakur R, Das A, Adhikari C, et al. Partitioning of prototropic species of an anticancer drug ellipticine in bile salt aggregates of different head groups and hydrophobic skeletons:a photophysical study to probe bile salts as multisite drug carriers. Phys Chem Chem Phys 2014;16:15681–91.
[2] Herfst S, Schrauwen EJ, Linster M, et al. Airborne transmission of influenza a/h5n1 virus between ferrets. Science 2012;336:1534–41.
[3] de Jong MD, Simmons CP, Thanh TT, et al. Fatal outcome of human influenza a(h5n1)is associated with high viral load and hypercytokinemia. Nat Med2006;12:1203–7.
[4] Edinger TO, Pohl MO, Stertz S. Entry of influenza a virus:host factors and antiviral targets. J General Virol 2014;95:263–77.
[5] Skehel JJ, Wiley DC. Receptor binding and membrane fusion in virus entry:the influenza hemagglutinin. Annu Rev Biochem 2000;69:531–69.
[6] Stauffer S, Feng Y, Nebioglu F, et al. Stepwise priming by acidic ph and a high K+concentration is required for efficient uncoating of influenza a virus cores after penetration. J Virol 2014;88:13029–46.
[7] Shulman NS, Kassaye SG, Winters MA, et al. More on the treatment-tropism relationship:the impact of prior antiretroviral treatment on hiv coreceptor tropism among subjects entering aids clinical trials group 175. J Infectious Dis2007;196:328–9.
[8] Sakaguchi T, Tu Q, Pinto LH, et al. The active oligomeric state of the minimalistic influenza virus m2 ion channel is a tetramer. Proc Natl Acad Sci USA 1997;94:5000–5.
[9] Schnell JR, Chou JJ. Structure and mechanism of the m2 proton channel of influenza a virus. Nature 2008;451:591–5.
[10] Kawano K, Yano Y, Matsuzaki K. A dimer is the minimal proton-conducting unit of the influenza a virus m2 channel. J Mol Biol 2014;426:2679–91.
[11] Tobler K, Kelly ML, Pinto LH, et al. Effect of cytoplasmic tail truncations on the activity of the m(2)ion channel of influenza a virus. J Virol 1999;73:9695–701.
[12] Kochendoerfer GG, Salom D, Lear JD, et al. Total chemical synthesis of the integral membrane protein influenza a virus m2:role of its c-terminal domain in tetramer assembly. Biochemistry 1999;38:11905–13.
[13] Holsinger LJ, Nichani D, Pinto LH, et al. Influenza a virus m2 ion channel protein:a structure-function analysis. J Virol 1994;68:1551–63.
[14] Ekanayake EV, Fu R, Cross TA. Structural influences:cholesterol, drug, and proton binding to full-length influenza a m2 protein. Biophys J2016;110:1391–9.
[15] Kim SS, Upshur MA, Saotome K, et al. Cholesterol-dependent conformational exchange of the c-terminal domain of the influenza a m2 protein.Biochemistry 2015;54:7157–67.
[16] Nguyen PA, Soto CS, Polishchuk A, et al. Ph-induced conformational change of the influenza m2 protein c-terminal domain. Biochemistry 2008;47:9934–6.
[17] Georgieva ER, Borbat PP, Norman HD, et al. Mechanism of influenza a m2transmembrane domain assembly in lipid membranes. Sci Rep 2015;5:11757.
[18] de Aguiar Vallim TQ, Tarling EJ, Edwards PA. Pleiotropic roles of bile acids in metabolism. Cell Metab 2013;17:657–69.
[19] Boatright JH, Nicker son JM, Moring AG, et al. Bile acids in treatment of ocular disease. J Ocular Biol Dis Informatics 2009;2:149–59.
[20] Ozcan U, Yilmaz E, Ozcan L, et al. Chemical chaperones reduce er stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science2006;313:1137–40.
[21] Yan H, Peng B, Liu Y, et al. Viral entry of hepatitis b and d viruses and bile salts transportation share common molecular determinants on sodium taurocholate cotransporting polypeptide. J Virol 2014;88:3273–84.
[22] Hassan IH, Zhang MS, Powers LS, et al. Influenza a viral replication is blocked by inhibition of the inositol-requiring enzyme 1(ire1)stress pathway. J Biol Chem 2012;287:4679–89.
[23] Hrincius ER, Liedmann S, Finkelstein D, et al. Acute lung injury results from innate sensing of viruses by an er stress pathway. Cell Rep 2015;11:1591–603.
[24] Matute-Bello G, Downey G, Moore BB, et al. An official american thoracic society workshop report:features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol 2011;44:725–38.
[25] Sulli C, Banik SS, Schilling J, et al. Detection of proton movement directly across viral membranes to identify novel influenza virus m2 inhibitors. J Virol2013;87:10679–86.
[26] Banerjee I, Yamauchi Y, Helenius A, et al. High-content analysis of sequential events during the early phase of influenza a virus infection. PLoS One 2013;8:e68450.
[27] Desplanques AS, Nauwynck HJ, Vercauteren D, et al. Plasma membrane cholesterol is required for efficient pseudorabies virus entry. Virology2008;376:339–45.
[28] Sun X, Whittaker GR. Role for influenza virus envelope cholesterol in virus entry and infection. J Virol 2003;77:12543–51.
[29] Fujioka Y, Tsuda M, Nanbo A, et al. A Ca2+dependent signalling circuit regulates influenza a virus internalization and infection. Nat Commun 2013;4:2763.
[30] Bechara C, Sagan S. Cell-penetrating peptides:20 years later, where do we stand? FEBS Lett 2013;587:1693–702.
[31] Guo Z, Peng H, Kang J, et al. Cell-penetrating peptides:possible transduction mechanisms and therapeutic applications. Biomed Rep 2016;4:528–34.
[32] Milletti F. Cell-penetrating peptides:classes, origin, and current landscape.Drug Discovery Today 2012;17:850–60.
[33] Claridge JK, Aittoniemi J, Cooper DM, et al. Isotropic bicelles stabilize the juxtamembrane region of the influenza m2 protein for solution nmr studies.Biochemistry 2013;52:8420–9.
[34] Rossman JS, Jing X, Leser GP, et al. Influenza virus m2 protein mediates escrtindependent membrane scission. Cell 2010;142:902–13.
[35] Shen H, Pirruccello M, De Camilli P. Snapshot:membrane curvature sensors and generators. Cell 2012;150:1300.
[36] Faustino C, Serafim C, Rijo P, et al. Bile acids and bile acid derivatives:use in drug delivery systems and as therapeutic agents. Expert Opin Drug Delivery2016;13:1133–48.
[37] Thakur R, Das A, Adhikari C, et al. Partitioning of prototropic species of an anticancer drug ellipticine in bile salt aggregates of different head groups and hydrophobic skeletons:a photophysical study to probe bile salts as multisite drug carriers. Phys Chem Chem Phys 2014;16:15681–91.