Rap1 GTPase drives assembly of the Mig-10/RIAM/Lamellipodin (MRL protein)–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 dephosphorylation 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, in part, to defective activation of integrins αLβ2 and α4β7. 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.
Phostensin enables lymphocyte integrin activation and population of peripheral lymphoid organs
Disclosures: The authors declare no competing interests exist.
- Award Id(s): P30CA062203
- Award Id(s): HL 139947,HL 151433
- Award Id(s): 902590
- Award Id(s): 18CDA34110228,14SDG18440023
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Ho-Sup Lee, Hao Sun, Frédéric Lagarrigue, Sarah Hyun Ji Kim, Jay W. Fox, Nicholas E. Sherman, Alexandre R. Gingras, Mark H. Ginsberg; Phostensin enables lymphocyte integrin activation and population of peripheral lymphoid organs. J Exp Med 1 August 2022; 219 (8): e20211637. doi: https://doi.org/10.1084/jem.20211637
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