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)

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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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Lymphocytes
Lymphocyte Function-Associated Antigen-1
Intercellular Adhesion Molecule-1
Leukocytes
Tail
Adhesion
Chemokines
Polarization
Ligands
Phenotype
Defects

Cite this

Pouwels, J., De Franceschi, N., Rantakari, P., Auvinen, K., Karikoski, M., Mattila, E., ... Ivaska, J. (2013). SHARPIN regulates uropod detachment in migrating lymphocytes. Cell Reports, 5(3), 619-628. https://doi.org/10.1016/j.celrep.2013.10.011
Pouwels, Jeroen ; De Franceschi, Nicola ; Rantakari, Pia ; Auvinen, Kaisa ; Karikoski, Marika ; Mattila, Elina ; Potter, Christopher ; Sundberg, John P. ; Hogg, Nancy ; Gahmberg, Carl G. ; Salmi, Marko ; Ivaska, Johanna. / SHARPIN regulates uropod detachment in migrating lymphocytes. In: Cell Reports. 2013 ; Vol. 5, No. 3. pp. 619-628.
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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.",
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Pouwels, J, De Franceschi, N, Rantakari, P, Auvinen, K, Karikoski, M, Mattila, E, Potter, C, Sundberg, JP, Hogg, N, Gahmberg, CG, Salmi, M & Ivaska, J 2013, 'SHARPIN regulates uropod detachment in migrating lymphocytes', Cell Reports, vol. 5, no. 3, pp. 619-628. https://doi.org/10.1016/j.celrep.2013.10.011

SHARPIN regulates uropod detachment in migrating lymphocytes. / Pouwels, Jeroen; De Franceschi, Nicola; Rantakari, Pia; Auvinen, Kaisa; Karikoski, Marika; Mattila, Elina; Potter, Christopher; Sundberg, John P.; Hogg, Nancy; Gahmberg, Carl G.; Salmi, Marko; Ivaska, Johanna (Corresponding Author).

In: Cell Reports, Vol. 5, No. 3, 2013, p. 619-628.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - SHARPIN regulates uropod detachment in migrating lymphocytes

AU - Pouwels, Jeroen

AU - De Franceschi, Nicola

AU - Rantakari, Pia

AU - Auvinen, Kaisa

AU - Karikoski, Marika

AU - Mattila, Elina

AU - Potter, Christopher

AU - Sundberg, John P.

AU - Hogg, Nancy

AU - Gahmberg, Carl G.

AU - Salmi, Marko

AU - Ivaska, Johanna

PY - 2013

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N2 - 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.

AB - 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.

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DO - 10.1016/j.celrep.2013.10.011

M3 - Article

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JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

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ER -

Pouwels J, De Franceschi N, Rantakari P, Auvinen K, Karikoski M, Mattila E et al. SHARPIN regulates uropod detachment in migrating lymphocytes. Cell Reports. 2013;5(3):619-628. https://doi.org/10.1016/j.celrep.2013.10.011