A herpesvirus virulence factor inhibits dendritic cell maturation through protein phosphatase 1 and Ikappa B kinase.
Dendritic cells are sentinels in innate and adaptive immunity. Upon virus infection, a complex program is in operation, which activates IκB kinase (IKK), a key regulator of inflammatory cytokines and costimulatory molecules. Here we show that the γ(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 γ(1)34.5-null mutant does not. Notably, γ(1)34.5 works in the absence of any other viral proteins. When expressed in mammalian cells, including dendritic cells, γ(1)34.5 associates with IKKα/β and inhibits NF-κB activation. This is mirrored by the inhibition of IKKα/β phosphorylation, p65/RelA phosphorylation, and nuclear translocation in response to lipopolysaccharide or poly(I:C) stimulation. Importantly, γ(1)34.5 recruits both IKKα/β and protein phosphatase 1, forming a complex that dephosphorylates two serine residues within the catalytic domains of IκB kinase. The amino-terminal domain of γ(1)34.5 interacts with IKKα/β, whereas the carboxyl-terminal domain binds to protein phosphatase 1. Deletions or mutations in either domain abolish the activity of γ(1)34.5. These results suggest that the control of IκB kinase dephosphorylation by γ(1)34.5 represents a critical viral mechanism to disrupt dendritic cell functions.
Department of Microbiology and Immunology (M/C 790), College of Medicine, University of Illinois, Chicago, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
Huali
H
Jin
Zhipeng
Z
Yan
Yijie
Y
Ma
Youjia
Y
Cao
Bin
B
He
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000502:physiology*; D006564:Herpesviridae / Q000472:pathogenicity*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007165:Immunosuppression Therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D017384:Sequence Deletion; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*
D050505:Mutant Proteins; D014764:Viral Proteins; D037521:Virulence Factors; C066469:gamma 34.5 protein, Human herpesvirus 1; D051550:I-kappa B Kinase; D054645:Protein Phosphatase 1
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