HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein.
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.
Orvedahl
Anthony
A
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Alexander
Diane
D
Tallóczy
Zsolt
Z
Sun
Qihua
Q
Wei
Yongjie
Y
Zhang
Wei
W
Burns
Dennis
D
Leib
David A
DA
Levine
Beth
B
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism / Q000821:virology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure / Q000821:virology; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D020798:Two-Hybrid System Techniques; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1; D019892:eIF-2 Kinase