The Influenza A Virus Protein PB1-F2: Killing Two Birds with One Stone?

Overview

Journal Virulence

Specialty Microbiology

Date 2011 Oct 6

PMID 21971186

Citations 21

Authors

Zsuzsanna T Varga

Peter Palese

Affiliations

Soon will be listed here.

Abstract

PB1-F2 is a 90 amino acid protein that is expressed from the +1 open reading frame in the PB1 gene of some influenza A viruses. The PB1-F2 protein has been shown to contribute to viral pathogenicity, but the molecular mechanisms for mediating virulence have been unclear. Previous reports demonstrate that PB1-F2 promotes cell death, causes immunopathology and increases pro-inflammatory responses. Our group has identified a single point mutation from asparagine (N) to serine (S) at position 66 in the PB1-F2 protein that dramatically increases the virulence of highly pathogenic avian H5N1 influenza viruses and of the 1918 pandemic strain. In search for the mechanism by which PB1-F2 N66S increases pathogenicity, we have identified and characterized a novel function of PB1-F2, i.e. interferon antagonism, both in vitro and in the mouse model. Here, we discuss a hypothesis for a possible molecular link between the pro-apoptotic and anti-interferon functions of PB1-F2.

Citing Articles

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References

Tang E, Wang C . MAVS self-association mediates antiviral innate immune signaling. J Virol. 2009; 83(8):3420-8. PMC: 2663242. DOI: 10.1128/JVI.02623-08. View

McAuley J, Zhang K, McCullers J . The effects of influenza A virus PB1-F2 protein on polymerase activity are strain specific and do not impact pathogenesis. J Virol. 2009; 84(1):558-64. PMC: 2798424. DOI: 10.1128/JVI.01785-09. View

Chattopadhyay S, Marques J, Yamashita M, Peters K, Smith K, Desai A . Viral apoptosis is induced by IRF-3-mediated activation of Bax. EMBO J. 2010; 29(10):1762-73. PMC: 2876960. DOI: 10.1038/emboj.2010.50. View

Chen W, Calvo P, Malide D, Gibbs J, Schubert U, Bacik I . A novel influenza A virus mitochondrial protein that induces cell death. Nat Med. 2001; 7(12):1306-12. DOI: 10.1038/nm1201-1306. View

Li H, Fujikura D, Harada T, Uehara J, Kawai T, Akira S . IPS-1 is crucial for DAP3-mediated anoikis induction by caspase-8 activation. Cell Death Differ. 2009; 16(12):1615-21. DOI: 10.1038/cdd.2009.97. View

Kochs G, Garcia-Sastre A, Martinez-Sobrido L . Multiple anti-interferon actions of the influenza A virus NS1 protein. J Virol. 2007; 81(13):7011-21. PMC: 1933316. DOI: 10.1128/JVI.02581-06. View

Zamarin D, Ortigoza M, Palese P . Influenza A virus PB1-F2 protein contributes to viral pathogenesis in mice. J Virol. 2006; 80(16):7976-83. PMC: 1563817. DOI: 10.1128/JVI.00415-06. View

Zhirnov O, Klenk H . Control of apoptosis in influenza virus-infected cells by up-regulation of Akt and p53 signaling. Apoptosis. 2007; 12(8):1419-32. DOI: 10.1007/s10495-007-0071-y. View

. Retracted article: MAVS protects cells from apoptosis by negatively regulating VDAC1. Mol Cell Biochem. 2010; 375(1-2):219. DOI: 10.1007/s11010-010-0658-4. View

10.

Lei Y, Moore C, Liesman R, OConnor B, Bergstralh D, Chen Z . MAVS-mediated apoptosis and its inhibition by viral proteins. PLoS One. 2009; 4(5):e5466. PMC: 2674933. DOI: 10.1371/journal.pone.0005466. View

11.

McAuley J, Hornung F, Boyd K, Smith A, McKeon R, Bennink J . Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia. Cell Host Microbe. 2007; 2(4):240-9. PMC: 2083255. DOI: 10.1016/j.chom.2007.09.001. View

12.

Hai R, Schmolke M, Varga Z, Manicassamy B, Wang T, Belser J . PB1-F2 expression by the 2009 pandemic H1N1 influenza virus has minimal impact on virulence in animal models. J Virol. 2010; 84(9):4442-50. PMC: 2863736. DOI: 10.1128/JVI.02717-09. View

13.

Gibbs J, Malide D, Hornung F, Bennink J, Yewdell J . The influenza A virus PB1-F2 protein targets the inner mitochondrial membrane via a predicted basic amphipathic helix that disrupts mitochondrial function. J Virol. 2003; 77(13):7214-24. PMC: 164823. DOI: 10.1128/jvi.77.13.7214-7224.2003. View

14.

Zamarin D, Garcia-Sastre A, Xiao X, Wang R, Palese P . Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog. 2005; 1(1):e4. PMC: 1238739. DOI: 10.1371/journal.ppat.0010004. View

15.

Onoguchi K, Onomoto K, Takamatsu S, Jogi M, Takemura A, Morimoto S . Virus-infection or 5'ppp-RNA activates antiviral signal through redistribution of IPS-1 mediated by MFN1. PLoS Pathog. 2010; 6(7):e1001012. PMC: 2908619. DOI: 10.1371/journal.ppat.1001012. View

16.

Wurzer W, Planz O, Ehrhardt C, Giner M, Silberzahn T, Pleschka S . Caspase 3 activation is essential for efficient influenza virus propagation. EMBO J. 2003; 22(11):2717-28. PMC: 158404. DOI: 10.1093/emboj/cdg279. View

17.

Hale B, Randall R, Ortin J, Jackson D . The multifunctional NS1 protein of influenza A viruses. J Gen Virol. 2008; 89(Pt 10):2359-2376. DOI: 10.1099/vir.0.2008/004606-0. View

18.

Yasukawa K, Oshiumi H, Takeda M, Ishihara N, Yanagi Y, Seya T . Mitofusin 2 inhibits mitochondrial antiviral signaling. Sci Signal. 2009; 2(84):ra47. DOI: 10.1126/scisignal.2000287. View

19.

Mazur I, Anhlan D, Mitzner D, Wixler L, Schubert U, Ludwig S . The proapoptotic influenza A virus protein PB1-F2 regulates viral polymerase activity by interaction with the PB1 protein. Cell Microbiol. 2008; 10(5):1140-52. DOI: 10.1111/j.1462-5822.2008.01116.x. View

20.

Conenello G, Zamarin D, Perrone L, Tumpey T, Palese P . A single mutation in the PB1-F2 of H5N1 (HK/97) and 1918 influenza A viruses contributes to increased virulence. PLoS Pathog. 2007; 3(10):1414-21. PMC: 2000966. DOI: 10.1371/journal.ppat.0030141. View