| pubmed-article:21248029 | pubmed:abstractText | Dendritic cells are sentinels in innate and adaptive immunity. Upon virus infection, a complex program is in operation, which activates I?B kinase (IKK), a key regulator of inflammatory cytokines and costimulatory molecules. Here we show that the ?(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 ?(1)34.5-null mutant does not. Notably, ?(1)34.5 works in the absence of any other viral proteins. When expressed in mammalian cells, including dendritic cells, ?(1)34.5 associates with IKK?/? and inhibits NF-?B activation. This is mirrored by the inhibition of IKK?/? phosphorylation, p65/RelA phosphorylation, and nuclear translocation in response to lipopolysaccharide or poly(I:C) stimulation. Importantly, ?(1)34.5 recruits both IKK?/? and protein phosphatase 1, forming a complex that dephosphorylates two serine residues within the catalytic domains of I?B kinase. The amino-terminal domain of ?(1)34.5 interacts with IKK?/?, whereas the carboxyl-terminal domain binds to protein phosphatase 1. Deletions or mutations in either domain abolish the activity of ?(1)34.5. These results suggest that the control of I?B kinase dephosphorylation by ?(1)34.5 represents a critical viral mechanism to disrupt dendritic cell functions. | lld:pubmed |
