TY - JOUR
T1 - Trif-related adapter molecule is phosphorylated by PKCε during Toll-like receptor 4 signaling
AU - McGettrick, Anne F.
AU - Brint, Elizabeth K.
AU - Palsson-McDermott, Eva M.
AU - Rowe, Daniel C.
AU - Golenbock, Douglas T.
AU - Gay, Nicholas J.
AU - Fitzgerald, Katherine A.
AU - O'Neill, Luke A.J.
PY - 2006/6/13
Y1 - 2006/6/13
N2 - PKCε has been shown to play a key role in the effect of the Gram-negative bacterial product LPS; however, the target for PKCε 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-β (Trif), and Trif-related adapter molecule (TRAM). Here we show that TRAM is transiently phosphorylated by PKCε 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 PKCε-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 PKCε.
AB - PKCε has been shown to play a key role in the effect of the Gram-negative bacterial product LPS; however, the target for PKCε 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-β (Trif), and Trif-related adapter molecule (TRAM). Here we show that TRAM is transiently phosphorylated by PKCε 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 PKCε-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 PKCε.
KW - Innate immunity
KW - LPS
KW - Myristoylation
UR - https://www.scopus.com/pages/publications/33745124663
U2 - 10.1073/pnas.0600462103
DO - 10.1073/pnas.0600462103
M3 - Article
C2 - 16757566
AN - SCOPUS:33745124663
SN - 0027-8424
VL - 103
SP - 9196
EP - 9201
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 24
ER -