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

Frontiers in Immunology

Stephan W. Morris¹  Markus Moser²  Sari Tojkander⁴  Sean Yao⁴  Liisa M. Uotila⁵  Susanna Carola Fagerholm⁵  Terhi Savinko⁵  Heidi Harjunpää⁵  Carla Guenther⁵  Marc Llort Asens⁵  Imrul Faisal⁵  Tiina Öhman⁶ 

[1] Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN, United States;Department of Molecular Medicine, Max Planck Institute of Biochemistry, Martinsried, Germany;Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, United States;Department of Veterinary Biosciences, University of Helsinki, Helsinki, Finland;Fagerholm Lab, MIBS, University of Helsinki, Helsinki, Finland;Institute of Biotechnology, University of Helsinki, Helsinki, Finland;

关键词: dendritic cells;    adhesion;    MRTF-A;    SRF;    MKL-1;    LAD-III;   

DOI  :  10.3389/fimmu.2019.01138

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown