Binder1BH.pdf (1.11 MB)
Download file

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

Download (1.11 MB)
journal contribution
posted on 27.05.2011, 00:00 by Huali Jin, Zhipeng Yan, Yijie Ma, Youjia Cao, Ben He
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.

Funding

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.).

History

Publisher Statement

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.

Publisher

American Society for Microbiology

Language

en_US

issn

0022-538X

Issue date

01/04/2011

Usage metrics

Categories

Keywords

Exports