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

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is a key regulator of T cell activation.
• PTPN22 dephosphorylates substrates in T cell receptor (TCR) signaling, inhibiting T cell activation.
• The PTPN22 gene is a major risk factor for autoimmune diseases.

Purpose of the Study:

• To investigate the regulatory mechanisms of PTPN22 activity and stability.
• To identify the specific phosphorylation sites on PTPN22 and their functional consequences.
• To explore the interaction between PTPN22 phosphorylation and its role in T cell signaling and autoimmunity.

Main Methods:

• Mass spectrometry was used to identify PTPN22 phosphorylation sites.
• Experiments were conducted in Jurkat and primary human T cells.
• T cells were activated using phorbol ester/ionomycin or anti-CD3/CD28 antibodies.

Main Results:

• PTPN22 was identified as being phosphorylated at Ser751 by PKCα in activated T cells.
• Phosphorylation at Ser751 prolonged PTPN22 half-life by inhibiting ubiquitination and plasma membrane recruitment.
• Ser751 phosphorylation enhanced PTPN22 interaction with CSK, an interaction impaired in the autoimmune-associated R620W variant.

Conclusions:

• Phosphorylation at Ser751 by PKCα is a critical regulatory mechanism for PTPN22.
• This phosphorylation influences PTPN22 stability and its translocation to TCR signaling complexes.
• Understanding PTPN22 phosphorylation provides insights into T cell regulation and autoimmune disease pathogenesis.