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An Herpesvirus Virulence Factor Inhibits Dendritic Cell Activation Through Protein Phosphatase 1 and IκB Kinase

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Title: An Herpesvirus Virulence Factor Inhibits Dendritic Cell Activation Through Protein Phosphatase 1 and IκB Kinase
Alternative Title: HSV and IκB kinase
Author(s): Jin, Huali; Yan, Zhipeng; Ma, Yijie; Cao, Youjia; He, Ben
Abstract: Dendritic cells are sentinels in innate and adaptive immunity. Upon virus infection, a complex program is in operation, which activates I kappa B kinase (IKK), a key regulator of inflammatory cytokines and costimulatory molecules. Here we show that the gamma(1)34.5 protein, a virulence factor of herpes simplex viruses, blocks Toll-like receptor-mediated dendritic cell maturation. While the wild-type virus inhibits the induction of major histocompatibility complex (MHC) class II, CD86, interleukin-6 (IL-6), and IL-12, the gamma(1)34.5-null mutant does not. Notably, gamma(1)34.5 works in the absence of any other viral proteins. When expressed in mammalian cells, including dendritic cells, gamma(1)34.5 associates with IKK alpha/beta and inhibits NF-kappa B activation. This is mirrored by the inhibition of IKK alpha/beta phosphorylation, p65/RelA phosphorylation, and nuclear translocation in response to lipopolysaccharide or poly(I:C) stimulation. Importantly, gamma(1)34.5 recruits both IKK alpha/beta and protein phosphatase 1, forming a complex that dephosphorylates two serine residues within the catalytic domains of I kappa B kinase. The amino-terminal domain of gamma(1)34.5 interacts with IKK alpha/beta, whereas the carboxyl-terminal domain binds to protein phosphatase 1. Deletions or mutations in either domain abolish the activity of gamma(1)34.5. These results suggest that the control of I kappa B kinase dephosphorylation by gamma(1)34.5 represents a critical viral mechanism to disrupt dendritic cell functions.
Issue Date: 2011-04
Publisher: American Society for Microbiology
Citation Info: Jin, H., Yan, Z., Ma, Y., Cao, Y., & He, B. 2011. An Herpesvirus Virulence Factor Inhibits Dendritic Cell Maturation Through Protein Phosphatase 1 and I{kappa}B Kinase. Journal of Virology 85(7): 3397-3407. DOI: 10.1128/JVI.02373-10
Type: Article
Description: Post print version of article may differ from published version. The definitive version is available through the American Society for Microbiology at DOI: 10.1128/JVI.02373-10.
URI: http://hdl.handle.net/10027/7715
ISSN: 0022-538X
Sponsor: This work was supported by grants from the National Institute of Allergy and Infectious Diseases (AI081711 to B.H) and the National Natural Science Foundation of China (30670080 & 111 to Y. C.).
Date Available in INDIGO: 2011-05-27
 

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