SHARPIN regulates uropod detachment in migrating lymphocytes.
SHARPIN-deficient mice display a multiorgan chronic inflammatory phenotype suggestive of altered leukocyte migration. We therefore studied the role of SHARPIN in lymphocyte adhesion, polarization, and migration. We found that SHARPIN 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. SHARPIN-deficient cells adhere better to ICAM-1 and show highly elongated tails when migrating. The increased tail lifetime in SHARPIN-deficient lymphocytes decreases the migration velocity. The adhesion, migration, and uropod defects in SHARPIN-deficient lymphocytes were rescued by reintroducing SHARPIN into the cells. Mechanistically, we show that SHARPIN 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, SHARPIN controls lymphocyte migration by endogenously maintaining LFA-1 inactive to allow adjustable detachment of the uropods in polarized cells.
Mesh Terms:
Amino Acid Sequence, Animals, Carrier Proteins, Cell Adhesion, Cell Movement, Cell Polarity, Cell Surface Extensions, HEK293 Cells, Humans, Lymphocyte Function-Associated Antigen-1, Lymphocytes, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Ubiquitins
Amino Acid Sequence, Animals, Carrier Proteins, Cell Adhesion, Cell Movement, Cell Polarity, Cell Surface Extensions, HEK293 Cells, Humans, Lymphocyte Function-Associated Antigen-1, Lymphocytes, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Ubiquitins
Cell Rep
Date: Nov. 14, 2013
PubMed ID: 24210817
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