Di Bartolo Vincenzo, Montagne Benjamin, Salek Mogjiborahman, Jungwirth Britta, Carrette Florent, Fourtane Julien, Sol-Foulon Nathalie, Michel Frédérique, Schwartz Olivier, Lehmann Wolf D, Acuto Oreste
Molecular Immunology Unit, Centre National de la Recherche Scientifique (CNRS) URA 1961, Institut Pasteur, 75724 Paris, Cedex 15, France.
J Exp Med. 2007 Mar 19;204(3):681-91. doi: 10.1084/jem.20062066. Epub 2007 Mar 12.
The SH2 domain-containing leukocyte protein of 76 kD (SLP-76) is a pivotal element of the signaling machinery controlling T cell receptor (TCR)-mediated activation. Here, we identify 14-3-3epsilon and zeta proteins as SLP-76 binding partners. This interaction was induced by TCR ligation and required phosphorylation of SLP-76 at serine 376. Ribonucleic acid interference and in vitro phosphorylation experiments showed that serine 376 is the target of the hematopoietic progenitor kinase 1 (HPK-1). Interestingly, either S376A mutation or HPK-1 knockdown resulted in increased TCR-induced tyrosine phosphorylation of SLP-76 and phospholipase C-gamma1. Moreover, an SLP-76-S376A mutant induced higher interleukin 2 gene transcription than wild-type SLP-76. These data reveal a novel negative feedback loop involving HPK-1-dependent serine phosphorylation of SLP-76 and 14-3-3 protein recruitment, which tunes T cell activation.
含SH2结构域的76kD白细胞蛋白（SLP - 76）是控制T细胞受体（TCR）介导的激活信号传导机制的关键元件。在此，我们鉴定出14 - 3 - 3ε和ζ蛋白为SLP - 76的结合伴侣。这种相互作用由TCR连接诱导，且需要SLP - 76在丝氨酸376处磷酸化。核糖核酸干扰和体外磷酸化实验表明，丝氨酸376是造血祖细胞激酶1（HPK - 1）的作用靶点。有趣的是，S376A突变或HPK - 1敲低均导致TCR诱导的SLP - 76和磷脂酶C - γ1酪氨酸磷酸化增加。此外，SLP - 76 - S376A突变体诱导的白细胞介素2基因转录高于野生型SLP - 76。这些数据揭示了一种新的负反馈回路，涉及HPK - 1依赖的SLP - 76丝氨酸磷酸化和14 - 3 - 3蛋白募集，从而调节T细胞激活。
