A beta2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation

Research output: Contribution to journalArticleScientificpeer-review

Abstract

beta2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of beta2-integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood. Here we demonstrate that mutation of the kindlin-3 binding site in the b2-integrin
(TTT/AAA-b2-integrin knock-in mouse/KI) abolishes activation of the actin-regulated myocardin related transcription factor A/serum response factor (MRTF-A/SRF) signaling pathway in dendritic cells and MRTF-A/SRF-dependent gene expression. We show that Ras homolog gene family, member A (RhoA) activation and filamentous-actin (F-actin) polymerization is abolished in murine TTT/AAA-b2-integrin KI dendritic cells, which leads to a failure ofMRTF-A to localize to the cell nucleus to coactivate genes together with SRF. In addition, we show that dendritic cell gene expression, adhesion and integrin-mediated traction forces on ligand coated surfaces is dependent on the MRTF-A/SRF signaling pathway. The participation of b2-integrin and kindlin-3-mediated cell adhesion in the regulation of the ubiquitous MRTF-A/SRF signaling pathway in immune cells may help explain the role of b2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function.
Original languageEnglish
Article number1138
JournalFrontiers in Immunology
Volume10
Issue number1138
Number of pages13
ISSN1664-3224
DOIs
Publication statusPublished - 28 May 2019
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 1182 Biochemistry, cell and molecular biology
  • DENDRITIC CELLS
  • ADHESION
  • MRTF-A/MAL-SRF pathway
  • LEUKOCYTE ADHESION DEFICIENCY
  • TRACTION FORCES
  • dendritic cells
  • adhesion
  • MRTF-A
  • SRF
  • MKL-1
  • LAD-III
  • traction force
  • SERUM RESPONSE
  • TRANSCRIPTION FACTOR
  • BETA-2 INTEGRINS
  • MYOCARDIN
  • MIGRATION
  • ACTIVATION
  • KINDLIN-3
  • SELECTINS
  • DYNAMICS

Cite this

@article{644106ab631a4416b7e32f42b3c5b8fc,
title = "A beta2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation",
abstract = "beta2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of beta2-integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood. Here we demonstrate that mutation of the kindlin-3 binding site in the b2-integrin(TTT/AAA-b2-integrin knock-in mouse/KI) abolishes activation of the actin-regulated myocardin related transcription factor A/serum response factor (MRTF-A/SRF) signaling pathway in dendritic cells and MRTF-A/SRF-dependent gene expression. We show that Ras homolog gene family, member A (RhoA) activation and filamentous-actin (F-actin) polymerization is abolished in murine TTT/AAA-b2-integrin KI dendritic cells, which leads to a failure ofMRTF-A to localize to the cell nucleus to coactivate genes together with SRF. In addition, we show that dendritic cell gene expression, adhesion and integrin-mediated traction forces on ligand coated surfaces is dependent on the MRTF-A/SRF signaling pathway. The participation of b2-integrin and kindlin-3-mediated cell adhesion in the regulation of the ubiquitous MRTF-A/SRF signaling pathway in immune cells may help explain the role of b2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function.",
keywords = "1182 Biochemistry, cell and molecular biology, DENDRITIC CELLS, ADHESION, MRTF-A/MAL-SRF pathway, LEUKOCYTE ADHESION DEFICIENCY, TRACTION FORCES, dendritic cells, adhesion, MRTF-A, SRF, MKL-1, LAD-III, traction force, SERUM RESPONSE, TRANSCRIPTION FACTOR, BETA-2 INTEGRINS, MYOCARDIN, MIGRATION, ACTIVATION, KINDLIN-3, SELECTINS, DYNAMICS",
author = "Carla Guenther and Imrul Faisal and Liisa Uotila and {Llort Asens}, Marc and Heidi Harjunp{\"a}{\"a} and Terhi Savinko and Tiina {\"O}hman and Sean Yao and Markus Moser and Morris, {Stephan W.} and Sari Tojkander and Susanna Fagerholm",
year = "2019",
month = "5",
day = "28",
doi = "10.3389/fimmu.2019.01138",
language = "English",
volume = "10",
journal = "Frontiers in Immunology",
issn = "1664-3224",
publisher = "Frontiers Media",
number = "1138",

}

A beta2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation. / Guenther, Carla; Faisal, Imrul; Uotila, Liisa; Llort Asens, Marc; Harjunpää, Heidi; Savinko, Terhi; Öhman, Tiina; Yao, Sean; Moser, Markus; Morris, Stephan W.; Tojkander, Sari; Fagerholm, Susanna.

In: Frontiers in Immunology, Vol. 10, No. 1138, 1138, 28.05.2019.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - A beta2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation

AU - Guenther, Carla

AU - Faisal, Imrul

AU - Uotila, Liisa

AU - Llort Asens, Marc

AU - Harjunpää, Heidi

AU - Savinko, Terhi

AU - Öhman, Tiina

AU - Yao, Sean

AU - Moser, Markus

AU - Morris, Stephan W.

AU - Tojkander, Sari

AU - Fagerholm, Susanna

PY - 2019/5/28

Y1 - 2019/5/28

N2 - beta2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of beta2-integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood. Here we demonstrate that mutation of the kindlin-3 binding site in the b2-integrin(TTT/AAA-b2-integrin knock-in mouse/KI) abolishes activation of the actin-regulated myocardin related transcription factor A/serum response factor (MRTF-A/SRF) signaling pathway in dendritic cells and MRTF-A/SRF-dependent gene expression. We show that Ras homolog gene family, member A (RhoA) activation and filamentous-actin (F-actin) polymerization is abolished in murine TTT/AAA-b2-integrin KI dendritic cells, which leads to a failure ofMRTF-A to localize to the cell nucleus to coactivate genes together with SRF. In addition, we show that dendritic cell gene expression, adhesion and integrin-mediated traction forces on ligand coated surfaces is dependent on the MRTF-A/SRF signaling pathway. The participation of b2-integrin and kindlin-3-mediated cell adhesion in the regulation of the ubiquitous MRTF-A/SRF signaling pathway in immune cells may help explain the role of b2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function.

AB - beta2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of beta2-integrin expression or function causes the immunodeficiency disorders, Leukocyte Adhesion Deficiency (LAD) type I and III. LAD-III is caused by mutations in an important integrin regulator, kindlin-3, but exactly how kindlin-3 regulates leukocyte adhesion has remained incompletely understood. Here we demonstrate that mutation of the kindlin-3 binding site in the b2-integrin(TTT/AAA-b2-integrin knock-in mouse/KI) abolishes activation of the actin-regulated myocardin related transcription factor A/serum response factor (MRTF-A/SRF) signaling pathway in dendritic cells and MRTF-A/SRF-dependent gene expression. We show that Ras homolog gene family, member A (RhoA) activation and filamentous-actin (F-actin) polymerization is abolished in murine TTT/AAA-b2-integrin KI dendritic cells, which leads to a failure ofMRTF-A to localize to the cell nucleus to coactivate genes together with SRF. In addition, we show that dendritic cell gene expression, adhesion and integrin-mediated traction forces on ligand coated surfaces is dependent on the MRTF-A/SRF signaling pathway. The participation of b2-integrin and kindlin-3-mediated cell adhesion in the regulation of the ubiquitous MRTF-A/SRF signaling pathway in immune cells may help explain the role of b2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function.

KW - 1182 Biochemistry, cell and molecular biology

KW - DENDRITIC CELLS

KW - ADHESION

KW - MRTF-A/MAL-SRF pathway

KW - LEUKOCYTE ADHESION DEFICIENCY

KW - TRACTION FORCES

KW - dendritic cells

KW - adhesion

KW - MRTF-A

KW - SRF

KW - MKL-1

KW - LAD-III

KW - traction force

KW - SERUM RESPONSE

KW - TRANSCRIPTION FACTOR

KW - BETA-2 INTEGRINS

KW - MYOCARDIN

KW - MIGRATION

KW - ACTIVATION

KW - KINDLIN-3

KW - SELECTINS

KW - DYNAMICS

U2 - 10.3389/fimmu.2019.01138

DO - 10.3389/fimmu.2019.01138

M3 - Article

VL - 10

JO - Frontiers in Immunology

JF - Frontiers in Immunology

SN - 1664-3224

IS - 1138

M1 - 1138

ER -