Trif-related adapter molecule is phosphorylated by PKC{epsilon} during Toll-like receptor 4 signaling.

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Proceedings of the National Academy of Sciences of the United States of America, ISSN: 0027-8424, Vol: 103, Issue: 24, Page: 9196-201

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10.1073/pnas.0600462103; 10.3410/f.1032741.374846
PMC1482589; 1482589
McGettrick, Anne F.; Brint, Elizabeth K.; Palsson-McDermott, Eva M.; Rowe, Daniel C.; Golenbock, Douglas T.; Gay, Nicholas J.; Fitzgerald, Katherine A.; O'Neill, Luke A. J.
Faculty of 1000, Ltd.; Proceedings of the National Academy of Sciences
Biochemistry, Genetics and Molecular Biology; Multidisciplinary; 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; Immunology and Infectious Disease; Life Sciences; Medicine and Health Sciences
article description
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.