Influenza A virus uses the aggresome processing machinery for host cell entry

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Science  24 Oct 2014:
Vol. 346, Issue 6208, pp. 473-477
DOI: 10.1126/science.1257037

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Flu mimics damaged proteins during entry

Viruses are master manipulators. The early stages of how flu viruses enter cells are very well understood, but Banerjee et al. describe a new wrinkle (see the Perspective by Rajsbaum and García-Sastre). It seems that the virus carries with it into the cell ubiquitin: a molecule involved in marking proteins for destruction. The virus then exploits host cell machinery involved in recognizing and dealing with damaged proteins to uncoat its own RNA genome, ready to continue its path toward successful infection.

Science, this issue p. 473; see also p. 427


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.

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