A β2-Integrin/MRTF-A/SRF Pathway Regulates Dendritic Cell Gene Expression, Adhesion, and Traction Force Generation.

Abstract

β2-integrins are essential for immune system function because they mediate immune cell adhesion and signaling. Consequently, a loss of β2-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 β2-integrin (TTT/AAA-β2-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-β2-integrin KI dendritic cells, which leads to a failure of MRTF-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 β2-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 β2-integrin and kindlin-3 in integrin-mediated gene regulation and immune system function.

• Authors: Carla Guenther, Imrul Faisal, Liisa M Uotila, Marc Llort Asens, Heidi Harjunpää, Terhi Savinko, Tiina Öhman, Sean Yao, Markus Moser, Stephan W Morris, Sari Tojkander, Susanna Carola Fagerholm
• Journal: Frontiers in immunology (Front Immunol) Vol. 10 Pg. 1138 ( 2019) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 31191527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD18 Antigens
• Cytoskeletal Proteins
• Mrtfa protein, mouse
• Serum Response Factor
• Srf protein, mouse
• Trans-Activators
• kindlin-3 protein, mouse
• rhoA GTP-Binding Protein

Topics

• Animals
• Biomechanical Phenomena
• CD18 Antigens (genetics, metabolism)
• Cell Adhesion (genetics)
• Cell Movement (genetics)
• Cells, Cultured
• Cytoskeletal Proteins (genetics, metabolism)
• Dendritic Cells (cytology, metabolism)
• Gene Expression Profiling (methods)
• Gene Ontology
• Gene Regulatory Networks
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Serum Response Factor (genetics, metabolism)
• Signal Transduction (genetics)
• Trans-Activators (genetics, metabolism)
• rhoA GTP-Binding Protein (genetics, metabolism)