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

PTPN22 phosphorylation acts as a molecular rheostat for the inhibition of TCR signaling. Sci Signal. 2020 Mar 17;13(623): Authors: Yang S, Svensson MND, Harder NHO, Hsieh WC, Santelli E, Kiosses WB, Moresco JJ, Yates JR, King CC, Liu L, Stanford SM, Bottini N 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 PKCĪ± 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 sig...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research