Title
Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling
UMMS Affiliation
Department of Medicine, Division of Infectious Diseases and Immunology
Date
6-8-2006
Document Type
Article
Medical Subject Headings
Adaptor Proteins, Signal Transducing; Adaptor Proteins, Vesicular Transport; Animals; Cell Membrane; Cells, Cultured; Fibroblasts; Humans; Isoenzymes; Lipopolysaccharides; Mice; Mice, Knockout; Phosphorylation; Protein Kinase C-epsilon; Receptors, Interleukin; Recombinant Fusion Proteins; Signal Transduction; Toll-Like Receptor 4
Disciplines
Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences
Abstract
PKCepsilon has been shown to play a key role in the effect of the Gram-negative bacterial product LPS; however, the target for PKCepsilon in LPS signaling is unknown. LPS signaling is mediated by Toll-like receptor 4, which uses four adapter proteins, MyD88, MyD88 adapter-like (Mal), Toll/IL-1R domain-containing adapter inducing IFN-beta (Trif), and Trif-related adapter molecule (TRAM). Here we show that TRAM is transiently phosphorylated by PKCepsilon on serine-16 in an LPS-dependent manner. Activation of IFN regulatory factor 3 and induction of the chemokine RANTES, which are both TRAM-dependent, were attenuated in PKCepsilon-deficient cells. TRAMS16A is inactive when overexpressed and is attenuated in its ability to reconstitute signaling in TRAM-deficient cells. We have therefore uncovered a key process in Toll-like receptor 4 signaling, identifying TRAM as the target for PKCepsilon.
Rights and Permissions
Citation: Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9196-201. Epub 2006 Jun 6. Link to article on publisher's site