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bioRxiv · 10.1101/214981

PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt

Uche, U.·Szymczak-Workman, A. L.·Grebinoski, S.·Piccirillo, A.·D'Cruz, L. M.·Kane, L. P.
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Abstract

Phosphatidylinositol-3 kinases (PI3Ks) modulate numerous cellular functions, including growth, proliferation and survival. Dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or Transmembrane Inhibitor of PI3K - TrIP) is a novel transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular \"p85-like\" domain with homology to the inter-SH2 domain of the regulatory subunit of PI3K. Although TrIP has been shown to bind to the p110 catalytic subunit of PI3K in fibroblasts, the mechanism by which TrIP functions is poorly understood. We show that both the kringle and \"p85-like\" domains are necessary for TrIP inhibition of PI3K. We also demonstrate that TrIP protein is down-modulated from the surface of T cells to allow T cell activation. In addition, we present evidence that the kringle domain may modulate TrIP function by binding an as-yet-unidentified ligand. Using an inducible knockout mouse model that we developed, we show that TrIP-deficient T cells exhibit more robust T cell activation, show a preference for Th1 polarization and can mediate clearance of Listeria monocytogenes infection faster than WT mice. Thus, TrIP is an important negative regulator of T cell activation and may represent a novel target for immune modulation therapies.

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Uche, U., Szymczak-Workman, A. L., Grebinoski, S., Piccirillo, A., D'Cruz, L. M., Kane, L. P.. 2017-11-06. PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt. https://doi.org/10.1101/214981

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