Attenuation of T cell receptor signaling by serine phosphorylation-mediated lysine 30 ubiquitination of SLP-76 protein.
SLP-76 (SH2 domain-containing leukocyte protein of 76 kDa) is an adaptor protein that is essential for T cell development and T cell receptor (TCR) signaling activation. Previous studies have identified an important negative feedback regulation of SLP-76 by HPK1 (hematopoietic progenitor kinase 1; MAP4K1)-induced Ser-376 phosphorylation. Ser-376 phosphorylation of SLP-76 mediates 14-3-3 binding, resulting in the attenuation of SLP-76 activation and downstream signaling; however, the underlying mechanism of this action remains unknown. Here, we report that phosphorylated SLP-76 is ubiquitinated and targeted for proteasomal degradation during TCR signaling. SLP-76 ubiquitination is mediated by Ser-376 phosphorylation. Furthermore, Lys-30 is identified as a ubiquitination site of SLP-76. Loss of Lys-30 ubiquitination of SLP-76 results in enhanced anti-CD3 antibody-induced ERK and JNK activation. These results reveal a novel regulation mechanism of SLP-76 by ubiquitination and proteasomal degradation of activated SLP-76, which is mediated by Ser-376 phosphorylation, leading to down-regulation of TCR signaling.
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Xiaohong
X
Wang
Ju-Pi
JP
Li
Li-Li
LL
Chiu
Joung-Liang
JL
Lan
Der-Yuan
DY
Chen
Jonathan
J
Boomer
Tse-Hua
TH
Tan
D048948:14-3-3 Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D059748:Proteolysis; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012694:Serine / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D054875:Ubiquitination / Q000502:physiology*
D048948:14-3-3 Proteins; D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D012694:Serine; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D046988:Proteasome Endopeptidase Complex