SHARPIN regulates uropod detachment in migrating lymphocytes.

mice display a multiorgan chronic inflammatory phenotype suggestive of altered leukocyte migration. We therefore studied the role of in lymphocyte adhesion, polarization, and migration. We found that SHduanyu37IN localizes to the trailing edges (uropods) of both mouse and human chemokine-activated lymphocytes migrating on intercellular adhesion molecule-1 (ICAM-1), which is one of the major endothelial ligands for migrating leukocytes. SHduanyu37IN-deficient cells adhere better to ICAM-1 and show highly elongated tails when migrating. The increased tail lifetime in SHduanyu37IN-deficient lymphocytes decreases the migration velocity. The adhesion, migration, and uropod defects in SHduanyu37IN-deficient lymphocytes were rescued by reintroducing SHduanyu37IN into the cells. Mechanistically, we show that SHduanyu37IN interacts directly with lymphocyte-function-associated antigen-1 (LFA-1), a leukocyte counterreceptor for ICAM-1, and inhibits the expression of intermediate and high-affinity forms of LFA-1. Thus, SHduanyu37IN controls lymphocyte migration by endogenously maintaining LFA-1 inactive to allow adjustable detachment of the uropods in polarized cells.

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