title: Influenza A virus uses the aggresome processing machinery for host cell entry.
abstract: During cell entry, capsids of incoming influenza A viruses (IAVs) must be uncoated before viral ribonucleoproteins (vRNPs) can enter the nucleus for replication. After hemagglutinin-mediated membrane fusion in late endocytic vacuoles, the vRNPs and the matrix proteins dissociate from each other and disperse within the cytosol. Here, we found that for capsid disassembly, IAV takes advantage of the host cell's aggresome formation and disassembly machinery. The capsids mimicked misfolded protein aggregates by carrying unanchored ubiquitin chains that activated a histone deacetylase 6 (HDAC6)-dependent pathway. The ubiquitin-binding domain was essential for recruitment of HDAC6 to viral fusion sites and for efficient uncoating and infection. That other components of the aggresome processing machinery, including dynein, dynactin, and myosin II, were also required suggested that physical forces generated by microtubule- and actin-associated motors are essential for IAV entry.
authors.affiliation: Institute of Biochemistry, Eidgenossische Technische Hochschule (ETH) Zurich, Switzerland.
authors.forename: Indranil
authors.initials: I
authors.lastname: Banerjee
authors.affiliation: Epigenetics, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Miyake
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, Switzerland.
authors.forename: Samuel Philip
authors.initials: SP
authors.lastname: Nobs
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schneider
authors.affiliation: Synthetic and Systems Biology Unit, Biological Research Center, Szeged, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Horvath
authors.affiliation: Institute of Molecular Health Sciences, ETH Zurich, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
authors.affiliation: Epigenetics, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. Faculty of Sciences, University of Basel, Basel, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthias
authors.affiliation: Institute of Biochemistry, Eidgenossische Technische Hochschule (ETH) Zurich, Switzerland. ari.helenius@bc.biol.ethz.ch yohei.yamauchi@bc.biol.ethz.ch.
authors.forename: Ari
authors.initials: A
authors.lastname: Helenius
authors.affiliation: Institute of Biochemistry, Eidgenossische Technische Hochschule (ETH) Zurich, Switzerland. ari.helenius@bc.biol.ethz.ch yohei.yamauchi@bc.biol.ethz.ch.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Yamauchi
mesh_terms: D000818:Animals; D002213:Capsid / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000821:virology; D000072159:Dynactin Complex; D004398:Dyneins / Q000378:metabolism; D055786:Gene Knockout Techniques; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000502:physiology*; D054884:Host-Pathogen Interactions; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D007251:Influenza, Human / Q000235:genetics / Q000378:metabolism / Q000821:virology*; D008561:Membrane Fusion / Q000235:genetics / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D024462:Myosin Type II / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012261:Ribonucleoproteins / Q000378:metabolism; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D012261:Ribonucleoproteins; D025801:Ubiquitin; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D024462:Myosin Type II; D004398:Dyneins