A genetically regulated SKAP2 switch modulates human T lymphocyte adhesion and migration
Mara Cetty Spinella, Francesco Gualdrini, Cristina Leoni, Jun Siong Low, Sara Polletti, Amy Kenyon, Samuele Mauri, Veronica Vallelonga, Mehrpouya Mostanfar, Matteo Pecoraro, Chiara Soriani, Roberta Marzi, Elena Grassi, Fabio Bedin, Elena Foli, Niccolò Bianchi, Emina Džafo, Sandra Jovic, Alessandro Cuomo, Simona Rodighiero, David Jarrossay, Federica Sallusto, Gioacchino Natoli, Silvia MonticelliGenome-wide association studies investigating autoimmune disorders may reveal previously unrecognized regulators of immune cell functions. A Crohn’s disease risk allele was associated with increased expression in T lymphocytes of the adapter protein Src kinase–associated phosphoprotein 2 (SKAP2), whose functional role in these cells is unknown. By analyzing T cells from individuals homozygous for either allelic variant or engineered to modulate SKAP2 endogenous levels, we found that SKAP2 promotes T cell adhesion while restraining migration, acting nonredundantly with its homologue SKAP1. Consistent with such functional differences, SKAP1 and SKAP2 displayed distinct activation-induced regulation as well as unique protein interactomes. Prolonged TCR activation triggered caspase-mediated SKAP2 cleavage, leading to the disassembly of its interactome and enabling a migratory program. Together, these findings identify SKAP2 as a genetically regulated modulator of T cell function whose expression and activity control the balance between adhesion and migration.