PTPN22 phosphorylation acts as a molecular rheostat for the inhibition of TCR signaling

Shen Yang, Mattias N.D. Svensson, Nathaniel H.O. Harder, Wan Chen Hsieh, Eugenio Santelli, William B. Kiosses, James J. Moresco, John R. Yates, Charles C. King, Lin Liu, Stephanie M. Stanford, Nunzio Bottini

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbereaaw8130
JournalScience signaling
Volume13
Issue number623
DOIs
StatePublished - Mar 17 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Yang, S., Svensson, M. N. D., Harder, N. H. O., Hsieh, W. C., Santelli, E., Kiosses, W. B., Moresco, J. J., Yates, J. R., King, C. C., Liu, L., Stanford, S. M., & Bottini, N. (2020). PTPN22 phosphorylation acts as a molecular rheostat for the inhibition of TCR signaling. Science signaling, 13(623), [eaaw8130]. https://doi.org/10.1126/scisignal.aaw8130