title: SHARPIN regulates uropod detachment in migrating lymphocytes.
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.
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, 20521, Turku, Finland.|Turku Centre for Biotechnology, University of Turku, 20521 Turku, Finland.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Pouwels
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, 20521, Turku, Finland.|Turku Centre for Biotechnology, University of Turku, 20521 Turku, Finland.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Franceschi
authors.affiliation: Medicity Research Laboratory, University of Turku, 20521 Turku, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Rantakari
authors.affiliation: Medicity Research Laboratory, University of Turku, 20521 Turku, Finland.|National Institute for Health and Welfare, Inflammatory Mechanisms unit, 20521 Turku, Finland.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Auvinen
authors.affiliation: Medicity Research Laboratory, University of Turku, 20521 Turku, Finland.
authors.forename: Marika
authors.initials: M
authors.lastname: Karikoski
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, 20521, Turku, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Mattila
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609 USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Potter
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609 USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Sundberg
authors.affiliation: Leukocyte Adhesion Laboratory, Cancer Research UK London Research Institute, London WC2A 3LY, UK.
authors.forename: Nancy
authors.initials: N
authors.lastname: Hogg
authors.affiliation: Division of Biochemistry and Biotechnology, Department of Biosciences, University of Helsinki, FI-00014 Helsinki, Finland.
authors.forename: Carl G
authors.initials: CG
authors.lastname: Gahmberg
authors.affiliation: Medicity Research Laboratory, University of Turku, 20521 Turku, Finland.|Department of Medical Biochemistry and Genetics, University of Turku, 20521 Turku, Finland.|National Institute for Health and Welfare, Inflammatory Mechanisms unit, 20521 Turku, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
authors.affiliation: Medical Biotechnology, VTT Technical Research Centre of Finland, 20521, Turku, Finland.|Turku Centre for Biotechnology, University of Turku, 20521 Turku, Finland.|Department of Biochemistry and Food Chemistry, University of Turku, 20521 Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology; D022081:Cell Surface Extensions / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D014452:Ubiquitins / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D016169:Lymphocyte Function-Associated Antigen-1; C575183:SHARPIN protein, human; C554944:Sipl1 protein, mouse; D014452:Ubiquitins