A novel pathway down-modulating T cell activation involves HPK-1-dependent recruitment of 14-3-3 proteins on SLP-76.
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.
Di Bartolo
Vincenzo
V
Molecular Immunology Unit, Centre National de la Recherche Scientifique (CNRS) URA 1961, Institut Pasteur, 75724 Paris, Cedex 15, France. vbartolo@pasteur.fr
Montagne
Benjamin
B
Salek
Mogjiborahman
M
Jungwirth
Britta
B
Carrette
Florent
F
Fourtane
Julien
J
Sol-Foulon
Nathalie
N
Michel
Frédérique
F
Schwartz
Olivier
O
Lehmann
Wolf D
WD
Acuto
Oreste
O
D048948:14-3-3 Proteins / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins; D012694:Serine; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases