PTPN22 Activates PI3K Pathway via 14-3-3τ in T Cells.

Abstract

The protein tyrosine phosphatase PTPN22 inhibits T cell activation by dephosphorylating some essential proteins in the TCR-mediated signaling pathway, and its negative regulatory function protects organisms from autoimmune disease. 14-3-3τ is an adaptor protein that regulates target protein function through its intracellular localization. In this study, we identified that PTPN22 binds to 14-3-3τ via the PTPN22-Ser640 phosphorylation side. PTPN22 binding to 14-3-3τ resulted in a 14-3-3τ-Tyr179 dephosphorylation, and reduced the association between 14-3-3τ and Shc, which competitively increased 14-3-3ζ binding to Shc and activated PI3K by bringing it to membrane. In addition, PTPN22 decreases the tyrosine phosphorylation of p110 to activate PI3K. These two pathways cooperatively affect PI3K activity and the expression of PI3K downstream proteins, such as phosphorylated Akt, mTOR and FoxO1, which inhibited the expression of some proinflammatory factors such as IL-1β, IL-2, IL-6, IFN-γ and TNF-α. Our research provides a preliminary theory for PTPN22 regulating T cell activation, development and immune response via the PI3K/Akt/mTOR pathway and brings a new clue to clarify the functions of PTPN22 in autoimmune diseases.