Open AccessPTPN22 phosphorylation acts as a molecular rheostat for the inhibition of TCR signaling
Author(s) -
Shen K. Yang,
Mattias 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
Publication year - 2020
Publication title -
science signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.659
H-Index - 154
eISSN - 1937-9145
pISSN - 1945-0877
DOI - 10.1126/scisignal.aaw8130
Subject(s) - phosphorylation , ptpn22 , jurkat cells , t cell receptor , microbiology and biotechnology , protein tyrosine phosphatase , biology , phosphatase , tyrosine phosphorylation , signal transduction , ionomycin , t cell , biochemistry , immunology , immune system , genotype , single nucleotide polymorphism , intracellular , gene
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 Ser 751 by PKCα in Jurkat and primary human T cells activated with phorbol ester/ionomycin or antibodies against CD3/CD28. The phosphorylation of PTPN22 at Ser 751 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 Ser 751 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 Ser 751 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 Ser 751 mediates a reciprocal regulation of PTPN22 stability versus translocation to TCR signaling complexes by CSK-dependent and CSK-independent mechanisms.