EPS8 facilitates uncoating of influenza A virus

Gloria P. Larson; Vy Tran; Shuiqìng Yú; Yíngyún Caì; Christina A. Higgins; Danielle M. Smith; Steven F. Baker; Sheli R. Radoshitzky; Jens H. Kuhn; Andrew Mehle

Orthomyxoviridae: Alphainfluenzavirus), like all viruses, largely depends upon existing cellular machinery to successfully complete these initial stages of infection. During the first step of infection, attachment, FLUAV hemagglutinin (HA) binds to the target cell via sialic acid linkages on host glycoproteins (Dou et al., 2018) . Virions are internalized via receptor-mediated endocytosis and less frequently through an alternative macropinocytosis pathway (Matlin et al., 1981; de Vries et al., 2011) . Once within endosomes, virions are trafficked towards the nucleus using the cytoskeletal components actin, dynein, and microtubules (Lakadamyali et al., 2003) . The endosome matures and acidifies during cellular trafficking, and the virion interior is also acidified through the function of the viral ion channel M2 (Pinto et al., 1992) . The low pH in the endosome causes conformational changes in HA that drive fusion of the viral and endosomal lipid membranes, while low pH within the virion causes the viral matrix protein M1 to dissociate from the inner membrane of the viral envelope (Bukrinskaya et al., 1982; Maeda and Ohnishi, 1980; Martin and Helenius, 1991; Zhirnov, 1990) . Fusion of the two membranes releases a capsid-like viral core consisting of viral ribonucleoproteins (vRNPs) enclosed in an M1 shelllike structure into the cytoplasm. This complex engages the cellular aggresome to complete uncoating, and the released vRNPs are imported into the nucleus by cellular karyopherins (Banerjee et al., 2014; Melen et al., 2003; O'Neill et al., 1995; Wang et al., 1997) . Once in the nucleus, a pioneering round of transcription occurs on the incoming vRNPs that initiates replication and secondary rounds of transcription of the viral genome.