HSVICP0 recruits USP7 to modulate TLR-mediated innate response

Sandrine Daubeuf, Divyendu Singh, Yaohong Tan, Hongiu Liu, Howard J. Federoff, William J. Bowers, Khaled Tolba

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

Pattern recognition receptors represent the first line of defense against invading pathogens. Herpes simplex virus (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 in flammatory response by blocking NF-κB 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 deubiquitinates TRAF6 and IKKγ, thus terminating TLR-mediated NF-κB 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. (Blood. 2009;113:3264-3275).

Original languageEnglish
Pages (from-to)3264-3275
Number of pages12
JournalBlood
Volume113
Issue number14
DOIs
StatePublished - Apr 2 2009

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Simplexvirus
Viruses
Chemical activation
Cytoplasm
TNF Receptor-Associated Factor 6
Immediate-Early Proteins
Pattern Recognition Receptors
Adaptive Immunity
Innate Immunity
Pathogens
Ligands
Blood
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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Daubeuf, S., Singh, D., Tan, Y., Liu, H., Federoff, H. J., Bowers, W. J., & Tolba, K. (2009). HSVICP0 recruits USP7 to modulate TLR-mediated innate response. Blood, 113(14), 3264-3275. https://doi.org/10.1182/blood-2008-07-168203

HSVICP0 recruits USP7 to modulate TLR-mediated innate response. / Daubeuf, Sandrine; Singh, Divyendu; Tan, Yaohong; Liu, Hongiu; Federoff, Howard J.; Bowers, William J.; Tolba, Khaled.

In: Blood, Vol. 113, No. 14, 02.04.2009, p. 3264-3275.

Research output: Contribution to journalArticle

Daubeuf, S, Singh, D, Tan, Y, Liu, H, Federoff, HJ, Bowers, WJ & Tolba, K 2009, 'HSVICP0 recruits USP7 to modulate TLR-mediated innate response', Blood, vol. 113, no. 14, pp. 3264-3275. https://doi.org/10.1182/blood-2008-07-168203
Daubeuf S, Singh D, Tan Y, Liu H, Federoff HJ, Bowers WJ et al. HSVICP0 recruits USP7 to modulate TLR-mediated innate response. Blood. 2009 Apr 2;113(14):3264-3275. https://doi.org/10.1182/blood-2008-07-168203
Daubeuf, Sandrine ; Singh, Divyendu ; Tan, Yaohong ; Liu, Hongiu ; Federoff, Howard J. ; Bowers, William J. ; Tolba, Khaled. / HSVICP0 recruits USP7 to modulate TLR-mediated innate response. In: Blood. 2009 ; Vol. 113, No. 14. pp. 3264-3275.
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