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

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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

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