Trif-related Adapter Molecule is Phosphorylated by PKC{epsilon} During Toll-like Receptor 4 Signaling

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Jun 8

PMID 16757566

Citations 46

Authors

Anne F Mcgettrick

Elizabeth K Brint

Eva M Palsson-McDermott

Daniel C Rowe

Douglas T Golenbock

Nicholas J Gay

Katherine A Fitzgerald

Luke A J ONeill

Affiliations

Soon will be listed here.

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.

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