Influenza Virus M2 Ion Channel Protein is Necessary for Filamentous Virion Formation

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 2010 Mar 12

PMID 20219914

Citations 117

Authors

Jeremy S Rossman

Xianghong Jing

George P Leser

Victoria Balannik

Lawrence H Pinto

Robert A Lamb

Affiliations

Soon will be listed here.

Abstract

Influenza A virus buds from cells as spherical (approximately 100-nm diameter) and filamentous (approximately 100 nm x 2 to 20 microm) virions. Previous work has determined that the matrix protein (M1) confers the ability of the virus to form filaments; however, additional work has suggested that the influenza virus M2 integral membrane protein also plays a role in viral filament formation. In examining the role of the M2 protein in filament formation, we observed that the cytoplasmic tail of M2 contains several sites that are essential for filament formation. Additionally, whereas M2 is a nonraft protein, expression of other viral proteins in the context of influenza virus infection leads to the colocalization of M2 with sites of virus budding and lipid raft domains. We found that an amphipathic helix located within the M2 cytoplasmic tail is able to bind cholesterol, and we speculate that M2 cholesterol binding is essential for both filament formation and the stability of existing viral filaments.

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References

Chen B, Leser G, Jackson D, Lamb R . The influenza virus M2 protein cytoplasmic tail interacts with the M1 protein and influences virus assembly at the site of virus budding. J Virol. 2008; 82(20):10059-70. PMC: 2566248. DOI: 10.1128/JVI.01184-08. View

Nguyen P, Soto C, Polishchuk A, Caputo G, Tatko C, Ma C . pH-induced conformational change of the influenza M2 protein C-terminal domain. Biochemistry. 2008; 47(38):9934-6. PMC: 2746938. DOI: 10.1021/bi801315m. View

Min C, Bang S, Cho B, Choi Y, Yang J, Lee S . Role of amphipathic helix of a herpesviral protein in membrane deformation and T cell receptor downregulation. PLoS Pathog. 2008; 4(11):e1000209. PMC: 2581436. DOI: 10.1371/journal.ppat.1000209. View

Saarikangas J, Zhao H, Pykalainen A, Laurinmaki P, Mattila P, Kinnunen P . Molecular mechanisms of membrane deformation by I-BAR domain proteins. Curr Biol. 2009; 19(2):95-107. DOI: 10.1016/j.cub.2008.12.029. View

de Meyer F, Smit B . Effect of cholesterol on the structure of a phospholipid bilayer. Proc Natl Acad Sci U S A. 2009; 106(10):3654-8. PMC: 2656135. DOI: 10.1073/pnas.0809959106. View

Gouttenoire J, Castet V, Montserret R, Arora N, Raussens V, Ruysschaert J . Identification of a novel determinant for membrane association in hepatitis C virus nonstructural protein 4B. J Virol. 2009; 83(12):6257-68. PMC: 2687391. DOI: 10.1128/JVI.02663-08. View

Zou P, Wu F, Lu L, Huang J, Chen Y . The cytoplasmic domain of influenza M2 protein interacts with caveolin-1. Arch Biochem Biophys. 2009; 486(2):150-4. DOI: 10.1016/j.abb.2009.02.001. View

Neumann G, Noda T, Kawaoka Y . Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature. 2009; 459(7249):931-9. PMC: 2873852. DOI: 10.1038/nature08157. View

Grantham M, Wu W, Lalime E, Lorenzo M, Klein S, Pekosz A . Palmitoylation of the influenza A virus M2 protein is not required for virus replication in vitro but contributes to virus virulence. J Virol. 2009; 83(17):8655-61. PMC: 2738213. DOI: 10.1128/JVI.01129-09. View

10.

Ma C, Polishchuk A, Ohigashi Y, Stouffer A, Schon A, Magavern E . Identification of the functional core of the influenza A virus A/M2 proton-selective ion channel. Proc Natl Acad Sci U S A. 2009; 106(30):12283-8. PMC: 2718339. DOI: 10.1073/pnas.0905726106. View

11.

Balannik V, Wang J, Ohigashi Y, Jing X, Magavern E, Lamb R . Design and pharmacological characterization of inhibitors of amantadine-resistant mutants of the M2 ion channel of influenza A virus. Biochemistry. 2009; 48(50):11872-82. PMC: 2794939. DOI: 10.1021/bi9014488. View

12.

Balannik V, Carnevale V, Fiorin G, Levine B, Lamb R, Klein M . Functional studies and modeling of pore-lining residue mutants of the influenza a virus M2 ion channel. Biochemistry. 2009; 49(4):696-708. PMC: 4924815. DOI: 10.1021/bi901799k. View

13.

Zhang J, Leser G, Pekosz A, Lamb R . The cytoplasmic tails of the influenza virus spike glycoproteins are required for normal genome packaging. Virology. 2001; 269(2):325-34. DOI: 10.1006/viro.2000.0228. View

14.

Zhang J, Pekosz A, Lamb R . Influenza virus assembly and lipid raft microdomains: a role for the cytoplasmic tails of the spike glycoproteins. J Virol. 2000; 74(10):4634-44. PMC: 111983. DOI: 10.1128/jvi.74.10.4634-4644.2000. View

15.

Egashira M, Gorbenko G, Tanaka M, Saito H, Molotkovsky J, Nakano M . Cholesterol modulates interaction between an amphipathic class A peptide, Ac-18A-NH2, and phosphatidylcholine bilayers. Biochemistry. 2002; 41(12):4165-72. DOI: 10.1021/bi011885+. View

16.

Bourmakina S, Garcia-Sastre A . Reverse genetics studies on the filamentous morphology of influenza A virus. J Gen Virol. 2003; 84(Pt 3):517-527. DOI: 10.1099/vir.0.18803-0. View

17.

Tian C, Gao P, Pinto L, Lamb R, Cross T . Initial structural and dynamic characterization of the M2 protein transmembrane and amphipathic helices in lipid bilayers. Protein Sci. 2003; 12(11):2597-605. PMC: 2366949. DOI: 10.1110/ps.03168503. View

18.

Takeda M, Leser G, Russell C, Lamb R . Influenza virus hemagglutinin concentrates in lipid raft microdomains for efficient viral fusion. Proc Natl Acad Sci U S A. 2003; 100(25):14610-7. PMC: 299746. DOI: 10.1073/pnas.2235620100. View

19.

Elleman C, Barclay W . The M1 matrix protein controls the filamentous phenotype of influenza A virus. Virology. 2004; 321(1):144-53. DOI: 10.1016/j.virol.2003.12.009. View

20.

Schwartz M, Chen J, Lee W, Janda M, Ahlquist P . Alternate, virus-induced membrane rearrangements support positive-strand RNA virus genome replication. Proc Natl Acad Sci U S A. 2004; 101(31):11263-8. PMC: 509192. DOI: 10.1073/pnas.0404157101. View