Phostensin Enables Lymphocyte Integrin Activation and Population of Peripheral Lymphoid Organs

Abstract

Rap1 GTPase drives assembly of the Mig-10/RIAM/lamellipodin-Integrin-Talin (MIT) complex that enables integrin-dependent lymphocyte functions. Here we used tandem affinity tag-based proteomics to isolate and analyze the MIT complex and reveal that Phostensin (PTSN), a regulatory subunit of protein phosphatase 1, is a component of the complex. PTSN mediates de-phosphorylation of Rap1 thereby preserving the activity and membrane localization of Rap1 to stabilize the MIT complex. CRISPR/Cas9-induced deletion of PPP1R18, which encodes PTSN, markedly suppresses integrin activation in Jurkat human T cells. We generated apparently healthy Ppp1r18-/- mice that manifest lymphocytosis and reduced population of peripheral lymphoid tissues ascribable to defective activation of integrins L{beta}2 and 4{beta}7. Ppp1r18-/- T cells exhibit reduced capacity to induce colitis in a murine adoptive transfer model. Thus, PTSN enables lymphocyte integrin-mediated functions by dephosphorylating Rap1 to stabilize the MIT complex. As a consequence, loss of PTSN ameliorates T cell-mediated colitis. SUMMARYPhostensin, a protein phosphatase 1 regulatory subunit, supports lymphocyte integrin-dependent functions by mediating dephosphorylation of Rap1 to stabilize the MIT complex thereby enabling the population of peripheral lymphoid organs and T cell-mediated colitis.