CARMA1的磷酸化在T细胞受体介导的NF-κB激活中起关键作用。

Phosphorylation of CARMA1 plays a critical role in T Cell receptor-mediated NF-kappaB activation.

作者信息

Matsumoto Reiko, Wang Donghai, Blonska Marzenna, Li Hongxiu, Kobayashi Masayuki, Pappu Bhanu, Chen Yuhong, Wang Demin, Lin Xin

机构信息

Department of Molecular and Cellular Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.

出版信息

Immunity. 2005 Dec;23(6):575-85. doi: 10.1016/j.immuni.2005.10.007.

DOI:10.1016/j.immuni.2005.10.007

PMID:16356856

Abstract

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.

摘要

CARMA1介导T细胞受体（TCR）诱导的核因子κB（NF-κB）激活。然而，在信号通路中TCR如何与CARMA1相连尚不清楚。在此，我们表明CARMA1在TCR-CD28共刺激后可被诱导磷酸化。这种磷酸化可能由蛋白激酶Cθ（PKCθ）诱导，因为PKCθ在体外和体内均可诱导CARMA1磷酸化。我们的结果表明，PKCθ诱导的CARMA1磷酸化可能发生在CARMA1连接区的丝氨酸552位点。重要的是，丝氨酸552发生突变的CARMA1突变体的表达，在缺乏CARMA1的T细胞中无法介导TCR诱导的NF-κB激活。这种CARMA1突变体的功能缺陷可能是由于该突变体无法在关键残基处被磷酸化，从而无法将下游信号成分募集到免疫突触中。总之，我们的研究提供了首个遗传学证据，证明CARMA1的磷酸化在TCR信号通路中起关键作用。