Autophagy protects against Sindbis virus infection of the central nervous system.
Autophagy functions in antiviral immunity. However, the ability of endogenous autophagy genes to protect against viral disease in vertebrates remains to be causally established. Here, we report that the autophagy gene Atg5 function is critical for protection against lethal Sindbis virus (SIN) infection of the mouse central nervous system. Inactivating Atg5 in SIN-infected neurons results in delayed clearance of viral proteins, increased accumulation of the cellular p62 adaptor protein, and increased cell death in neurons, but the levels of viral replication remain unaltered. In vitro, p62 interacts with SIN capsid protein, and genetic knockdown of p62 blocks the targeting of viral capsid to autophagosomes. Moreover, p62 or autophagy gene knockdown increases viral capsid accumulation and accelerates virus-induced cell death without affecting virus replication. These results suggest a function for autophagy in mammalian antiviral defense: a cell-autonomous mechanism in which p62 adaptor-mediated autophagic viral protein clearance promotes cell survival.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Anthony
A
Orvedahl
Sarah
S
MacPherson
Rhea
R
Sumpter
Zsolt
Z
Tallóczy
Zhongju
Z
Zou
Beth
B
Levine
D018354:Alphavirus Infections / Q000276:immunology*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002460:Cell Line; D002490:Central Nervous System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000502:physiology*; D009474:Neurons / Q000473:pathology / Q000821:virology; D012845:Sindbis Virus / Q000276:immunology*; D016019:Survival Analysis
C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins