Journal
CELL HOST & MICROBE
Volume 1, Issue 1, Pages 23-35Publisher
CELL PRESS
DOI: 10.1016/j.chom.2006.12.001
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Funding
- NEI NIH HHS [P30-EY02687, R01 EY09083, R01 EY009083, T32 EY13360-06] Funding Source: Medline
- NIAID NIH HHS [R01 AI051367, T32 AI007520] Funding Source: Medline
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Autophagy is postulated to play a role in antiviral innate immunity. However, it is unknown whether viral evasion of autophagy is important in disease pathogenesis. Here we show that the herpes simplex virus type 1 (HSV-1)-encoded neurovirulence protein ICP34.5 binds to the mammalian autophagy protein Beclin 1 and inhibits its autophagy function. A mutant HSV-1 virus lacking the Beclin 1-binding domain of ICP34.5 fails to inhibit autophagy in neurons and demonstrates impaired ability to cause lethal encephalitis in mice. The neurovirulence of this Beclin 1-binding mutant virus is restored in pkr(-/-) mice. Thus, ICP34.5-mediated antagonism of the autophagy function of Beclin 1 is essential for viral neurovirulence, and the antiviral signaling molecule PKR lies genetically upstream of Beclin 1 in host defense against HSV-1. Our findings suggest that autophagy inhibition is a novel molecular mechanism by which viruses evade innate immunity and cause fatal disease.
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