TY - JOUR
T1 - PTPN22 phosphorylation acts as a molecular rheostat for the inhibition of TCR signaling
AU - Yang, Shen
AU - Svensson, Mattias N.D.
AU - Harder, Nathaniel H.O.
AU - Hsieh, Wan Chen
AU - Santelli, Eugenio
AU - Kiosses, William B.
AU - Moresco, James J.
AU - Yates, John R.
AU - King, Charles C.
AU - Liu, Lin
AU - Stanford, Stephanie M.
AU - Bottini, Nunzio
N1 - Funding Information:
This study was supported by grant R01 AI070544 from the NIH (to N.B.), 1-15-INI-13 from the American Diabetes Association (to S.M.S.), and NIH P41 GM103533 from the NIH (to J.R.Y.).
Publisher Copyright:
Copyright © 2020 The Authors, some rights reserved.
PY - 2020/3/17
Y1 - 2020/3/17
N2 - 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.
AB - 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.
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U2 - 10.1126/scisignal.aaw8130
DO - 10.1126/scisignal.aaw8130
M3 - Article
C2 - 32184287
AN - SCOPUS:85081994964
VL - 13
JO - Science's STKE : signal transduction knowledge environment
JF - Science's STKE : signal transduction knowledge environment
SN - 1937-9145
IS - 623
M1 - eaaw8130
ER -