Submitted July 15, 2008
Accepted September 30, 2008
HSV ICP0 recruits USP7 to modulate TLR-mediated innate response
Sandrine Daubeuf, Divyendu Singh, Yaohong Tan, Hongiu Liu, Howard J Federoff, William J Bowers, and Khaled Tolba*
IPBS, CNRS UMR5089, Toulouse, France
Division of Hematology-Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, United States
Georgetown University Medical Center, Washington, D.C., United States
Department of Neurology, Center for Aging and Developmental Biology, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
* Corresponding author; email: ktolba{at}mac.com.
Pattern recognition receptors represent the first line of defense against invading pathogens. HSV encodes multiple ligands detected by these receptors, yet persists in the majority of infected individuals indicating a breakdown in host defense against the virus. Here we identify a novel mechanism through which HSV immediate-early protein ICP0 inhibits TLR-dependent inflammatory response by blocking NF-
B and JNK activation downstream of TLR signal activation. This process depends on ICP0 mediated translocation of USP7 (HAUSP) from the nucleus to cytoplasm. We show that nuclear USP7 migrates to the cytoplasm in response to TLR engagement, a process that contributes to termination of TLR response. Cytoplasmic USP7 binds to and de-ubiquitinates TRAF6 and IKK
, thus terminating TLR mediated NF-B and JNK activation. These findings suggest that USP7 is part of a negative feedback loop regulating TLR signaling and that ICP0 exploits this physiologic process to attenuate innate response to HSV. ICP0 inhibition of the TLR response serves to uncouple the innate and adaptive immune response, thereby playing a key role in HSV pathogenesis and persistence.
