TY - JOUR
T1 - HSV-1 ICP34.5 Confers Neurovirulence by Targeting the Beclin 1 Autophagy Protein
AU - Orvedahl, Anthony
AU - Alexander, Diane
AU - Tallóczy, Zsolt
AU - Sun, Qihua
AU - Wei, Yongjie
AU - Zhang, Wei
AU - Burns, Dennis
AU - Leib, David A.
AU - Levine, Beth
N1 - Funding Information:
This work was supported by NIH grants RO1 AI051367 (B.L.), T32 AI007520 (A.O.), RO1 EY09083 (D.A.L.), and T32 EY13360-06 (D.A.); an Ellison Medical Foundation Senior Scholars Award in Infectious Diseases (B.L., A.O.); a Lew Wasserman Scholarship from Research to Prevent Blindness (D.A.L.); and core grants to the Department of Ophthalmology from the NIH (P30-EY02687) and Research to Prevent Blindness (D.A.L.). We thank Bernard Roizman for sharing unpublished data and reagents; Luis Parada, Bin He, and Sangita Sinha for helpful advice; Ian Mohr and Richard Thompson for providing antibodies and virus strains; Kristy Brown for assistance with electron microscopy; Yajuan Liu and Zhongju Zou for excellent technical assistance; and Frederick Scott and Renee Talley for administrative assistance.
PY - 2007/3/15
Y1 - 2007/3/15
N2 - 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.
AB - 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.
KW - MICROBIO
UR - http://www.scopus.com/inward/record.url?scp=33947715151&partnerID=8YFLogxK
U2 - 10.1016/j.chom.2006.12.001
DO - 10.1016/j.chom.2006.12.001
M3 - Article
C2 - 18005679
AN - SCOPUS:33947715151
SN - 1931-3128
VL - 1
SP - 23
EP - 35
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 1
ER -