SHARPIN regulates uropod detachment in migrating lymphocytes

Jeroen Pouwels, Nicola De Franceschi, Pia Rantakari, Kaisa Auvinen, Marika Karikoski, Elina Mattila, Christopher Potter, John P. Sundberg, Nancy Hogg, Carl G. Gahmberg, Marko Salmi, Johanna Ivaska (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

34 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)619-628
JournalCell Reports
Volume5
Issue number3
DOIs
Publication statusPublished - 2013
MoE publication typeA1 Journal article-refereed

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