TY - JOUR
T1 - Autophagy Protects against Sindbis Virus Infection of the Central Nervous System
AU - Orvedahl, Anthony
AU - MacPherson, Sarah
AU - Sumpter, Rhea
AU - Tallóczy, Zsolt
AU - Zou, Zhongju
AU - Levine, Beth
N1 - Funding Information:
We thank Diane Griffin, David Leib, Margaret MacDonald, Noboru Mizushima, Victor Stollar, and Tamotsu Yoshimori for providing critical reagents. We thank Abhijit Bugde and Kate Luby-Phelps for assistance with live cell imaging and Laurie Mueller for assistance with electron microscopy. This work was supported by the Ellison Medical Foundation Senior Scholars Award in Infectious Diseases (B.L.), NIH RO1 AI151367 (B.L.), and NIH T32 AI007520 (A.O.).
PY - 2010/2/18
Y1 - 2010/2/18
N2 - 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.
AB - 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.
KW - MICROBIO
KW - MOLIMMUNO
KW - MOLNEURO
UR - http://www.scopus.com/inward/record.url?scp=76249112828&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2010.01.007
DO - 10.1016/j.chom.2010.01.007
M3 - Article
C2 - 20159618
AN - SCOPUS:76249112828
SN - 1931-3128
VL - 7
SP - 115
EP - 127
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 2
ER -