Attenuation of T Cell Receptor Signaling by Serine Phosphorylation-mediated Lysine 30 Ubiquitination of SLP-76 Protein |
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| Authors: | Xiaohong Wang Ju-Pi Li Li-Li Chiu Joung-Liang Lan Der-Yuan Chen Jonathan Boomer Tse-Hua Tan |
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| Affiliation: | From the ‡Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030.;the §Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan.;the ¶Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung 40705, Taiwan, and ;the ‖Faculty of Medicine, National Yang-Ming University, Taipei 11221, Taiwan |
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| Abstract: | 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. |
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| Keywords: | Adaptor Proteins Serine/Threonine Protein Kinase Signal Transduction T Cell Ubiquitination SLP-76 |
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