Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaB activation.
CARMA1 mediates T cell receptor (TCR)-induced NF-kappaB activation. However, how TCR links to CARMA1 in the signaling pathway is not clear. Here, we show that CARMA1 is inducibly phosphorylated after TCR-CD28 costimulation. This phosphorylation is likely induced by PKCtheta, since PKCtheta induces phosphorylation of CARMA1 in vitro and in vivo. Our results indicate that the PKCtheta-induced phosphorylation of CARMA1 likely occurs on Ser552 on the Linker region of CARMA1. Importantly, expression of CARMA1 mutant, in which Ser552 is mutated, fails to mediate TCR-induced NF-kappaB activation in CARMA1-deficient T cells. The functional defect of this CARMA1 mutant is likely due to the fact that this mutant cannot be phosphorylated at the critical residue, thereby failing to recruit the downstream signaling components into the immunological synapse. Together, our studies provide the first genetic evidence that the phosphorylation of CARMA1 plays a critical role in the TCR signaling pathway.
Matsumoto
Reiko
R
Department of Molecular and Cellular Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Wang
Donghai
D
Blonska
Marzenna
M
Li
Hongxiu
H
Kobayashi
Masayuki
M
Pappu
Bhanu
B
Chen
Yuhong
Y
Wang
Demin
D
Lin
Xin
X
D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D018106:CD28 Antigens / Q000378:metabolism; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D040461:Gene Components; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics / Q000276:immunology*; D008156:Luciferases; D013058:Mass Spectrometry; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000276:immunology*; D015533:Transcriptional Activation / Q000276:immunology*
D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D018106:CD28 Antigens; C496467:Card11 protein, mouse; D016328:NF-kappa B; D011948:Receptors, Antigen, T-Cell; D008156:Luciferases; D011493:Protein Kinase C; D051528:Guanylate Kinases