PTPN22 phosphorylation acts as a molecular rheostat for the inhibition of TCR signaling
- 17 March 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Signaling
- Vol. 13 (623)
- https://doi.org/10.1126/scisignal.aaw8130
Abstract
The hematopoietic-specific protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is encoded by a major autoimmunity risk gene. PTPN22 inhibits T cell activation by dephosphorylating substrates involved in proximal T cell receptor (TCR) signaling. Here, we found by mass spectrometry that PTPN22 was phosphorylated at Ser751 by PKCα in Jurkat and primary human T cells activated with phorbol ester/ionomycin or antibodies against CD3/CD28. The phosphorylation of PTPN22 at Ser751 prolonged its half-life by inhibiting K48-linked ubiquitination and impairing recruitment of the phosphatase to the plasma membrane, which is necessary to inhibit proximal TCR signaling. Additionally, the phosphorylation of PTPN22 at Ser751 enhanced the interaction of PTPN22 with the carboxyl-terminal Src kinase (CSK), an interaction that is impaired by the PTPN22 R620W variant associated with autoimmune disease. The phosphorylation of Ser751 did not affect the recruitment of PTPN22 R620W to the plasma membrane but protected this mutant from degradation. Together, out data indicate that phosphorylation at Ser751 mediates a reciprocal regulation of PTPN22 stability versus translocation to TCR signaling complexes by CSK-dependent and CSK-independent mechanisms.Keywords
Funding Information
- American Diabetes Association (1-15-INI-13)
- National Institute of Allergy and Infectious Diseases (AI070544)
- National Institute of Allergy and Infectious Diseases (AI148073)
This publication has 49 references indexed in Scilit:
- A disease-associated PTPN22 variant promotes systemic autoimmunity in murine modelsJCI Insight, 2013
- The Autoimmunity Risk Variant LYP-W620 Cooperates with CSK in the Regulation of TCR SignalingPLOS ONE, 2013
- Lack of the Phosphatase PTPN22 Increases Adhesion of Murine Regulatory T Cells to Improve Their Immunosuppressive FunctionScience Signaling, 2012
- LYP inhibits T-cell activation when dissociated from CSKNature Chemical Biology, 2012
- Autoimmune-associated PTPN22 R620W Variation Reduces Phosphorylation of Lymphoid Phosphatase on an Inhibitory Tyrosine ResidueOnline Journal of Public Health Informatics, 2010
- A loss-of-function variant of PTPN22 is associated with reduced risk of systemic lupus erythematosusHuman Molecular Genetics, 2008
- Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseasesProceedings of the National Academy of Sciences of the United States of America, 2007
- Protein tyrosine phosphatases: from genes, to function, to diseaseNature Reviews Molecular Cell Biology, 2006
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001
- Protein kinase Cθ: a new essential superstar on the T-cell stageImmunology Today, 2000