Editors' ChoiceHost-Pathogen Interactions

Autophagic Machinery Promotes Viral Budding

Science Signaling  25 Feb 2014:
Vol. 7, Issue 314, pp. ec56
DOI: 10.1126/scisignal.2005212

Viruses and bacteria have not only evolved mechanisms for avoiding destruction by autophagy; some also coopt the autophagy machinery for their own benefit. Beale et al. report that the influenza A virus (IAV) ion channel protein Matrix 2 (M2) recruited the autophagosome marker LC3 to the plasma membrane to facilitate the production of stable virions. LC3 localizes to autophagosomal membranes and serves as a docking site for “cargo receptors,” which are proteins that bind to substrates destined for autophagic degradation. Whereas fluorescently tagged LC3 was distributed throughout the cytoplasm and on autophagosomes in uninfected human A549 and HCT116 cells, LC3 accumulated perinuclearly and at the plasma membrane after infection with the H1N1 strain of IAV. Infection with IAV lacking M2 did not induce accumulation of LC3 at the plasma membrane. The authors identified a putative LC3-interacting region (LIR) in the cytoplasmic tail of M2 and demonstrated that this motif mediated binding of M2 to LC3 in vitro. The M2 LIR was required for the recruitment of LC3 to the plasma membrane upon infection but was not required for the perinuclear accumulation of LC3 in infected cells. Depending on the viral strain, IAV can bud as filaments or as spheres, with filamentous budding requiring more host cell membrane resources than spherical budding. Cells infected with the filamentously budding PR8-MUd strain IAV containing mutations in the M2 LIR produced fewer filaments than cells infected with wild-type PR8-MUd IAV. Viral replication was unaffected by mutations in the M2 LIR, but the infectivity of viral particles was reduced with mutations in the M2 LIR. When left at room temperature for 1 to 2 days, supernatants from cells infected with M2 LIR–mutant IAV contained fewer plaque-forming units than supernatants from wild-type IAV. This decrease in infectivity was more pronounced with the filamentous IAV strain than with a nonfilamentous strain. Thus, M2 recruitment of LC3 to the plasma membrane may help mobilize membrane resources that contribute to the stability of virus particles. The ion channel activity of M2 is required for viral entry, and M2 blocks the fusion of autophagosomes with lysosomes, leading to perinuclear accumulation of autophagosomes (see commentary by Münz). This newly identified role for M2 adds another important virulence function to this multifunctional protein's repertoire.

R. Beale, H. Wise, A. Stuart, B. J. Ravenhill, P. Digard, F. Randow, A LC3-interacting motif in the influenza A virus M2 protein is required to subvert autophagy and maintain virion stability. Cell Host Microbe 15, 239–247 (2014). [PubMed]

C. Münz, Influenza A virus lures autophagic protein LC3 to budding sites. Cell Host Microbe 15, 130–131 (2014). [PubMed]