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

Phosphorylation of PTPN22 at Ser751 balances phosphatase degradation and plasma membrane recruitment. A switch for stability and function The protein tyrosine phosphatase PTPN22 limits T cell receptor (TCR) signaling, and polymorphisms in the PTPN22 locus are associated with an increased risk of autoimmune diseases. Yang et al. showed that phosphorylation of Ser751 protected PTPN22 from degradation by preventing its ubiquitination. Phosphorylation of this site limited the ability of PTPN22 to inhibit TCR signaling by keeping it away from the plasma membrane (where active TCR is located). Phosphorylation of Ser751 enhanced the interaction of PTPN22 with the kinase CSK, and disruption of this interaction promotes the plasma membrane localization of the phosphatase. These results demonstrate how a single phosphorylation event is a switch for the stability and function of PTPN22, an important brake on TCR signaling. 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.