Protein kinase Cdelta binds TIRAP/Mal to participate in TLR signaling.
Toll-like receptor (TLR) family members recognize specific molecular patterns within pathogens. Signaling through TLRs results in a proximal event that involves direct binding of adaptor proteins to the receptors. We observed that TIRAP/Mal, an adaptor protein for TLR2 and TLR4, binds protein kinase Cdelta (PKCdelta). TIRAP/Mal GST-fusion protein and a TIRAP/Mal antibody were able to precipitate PKCdelta from rat peritoneal macrophage and THP1 cell lysates. Truncation mutants of TIRAP/Mal showed that the TIR domain of TIRAP/Mal is responsible for binding. TLR2- and TLR4-mediated phosphorylation of p38 MAPK, IKK, and IkappaB in RAW264.7 cells were abolished by depletion of PKCdelta. These results suggest that PKCdelta binding to TIRAP/Mal promotes TLR signaling events.
Kubo-Murai
Miho
M
The Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
Hazeki
Kaoru
K
Sukenobu
Naoe
N
Yoshikawa
Kyoko
K
Nigorikawa
Kiyomi
K
Inoue
Kazumi
K
Yamamoto
Toshiyoshi
T
Matsumoto
Misako
M
Seya
Tsukasa
T
Inoue
Norimitsu
N
Hazeki
Osamu
O
D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000187:drug effects; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; C434984:TIRAP protein, human; D051193:Toll-Like Receptors; D005982:Glutathione Transferase; C081975:protein kinase C eta; D051550:I-kappa B Kinase; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases