A Mechanosensitive RhoA Pathway that Protects Epithelia against Acute Tensile Stress

• DOI: 10.1016/j.devcel.2018.09.016
• Publication Date: 2018-10-11T14:37:16Z
• Authors: Bipul R. Acharya; Alexander Nestor-...; Xuan Liang; Shafali Gupta; Kinga Duszyc; Estelle Gauquelin; Guillermo A. Gomez; Srikanth Budnar; Philippe Marcq; Oliver E. Jensen; Zev Bryant; Alpha S. Yap
• Keywords: 571; 1300 Biochemistry; Genetics and Molecular Biology; Zonula Adherens; Epithelium; 1307 Cell Biology; 1309 Developmental Biology; Tensile Strength; 1312 Molecular Biology; Humans; Actin; mechanotransduction; Myosin-Vi; Cell-Cell Junctions; E-Cadherin Junctions; Migrating Cells; RhoA; Epithelial Cells; Actomyosin; Adherens Junctions; tension; Cadherins; Beta-Catenin; Actins; [SDV] Life Sciences [q-bio]; Cytoplasmic Domain; Actin Cytoskeleton; Myosin VI; Alpha-Catenin; Epithelia; Stress, Mechanical; rhoA GTP-Binding Protein

Adherens junctions are tensile structures that couple epithelial cells together. Junctional tension can arise from cell-intrinsic application of contractility or from the cell-extrinsic forces of tissue movement. Here, we report a mechanosensitive signaling pathway that activates RhoA at adherens junctions to preserve epithelial integrity in response to acute tensile stress. We identify Myosin VI as the force sensor, whose association with E-cadherin is enhanced when junctional tension is increased by mechanical monolayer stress. Myosin VI promotes recruitment of the heterotrimeric Gα12 protein to E-cadherin, where it signals for p114 RhoGEF to activate RhoA. Despite its potential to stimulate junctional actomyosin and further increase contractility, tension-activated RhoA signaling is necessary to preserve epithelial integrity. This is explained by an increase in tensile strength, especially at the multicellular vertices of junctions, that is due to mDia1-mediated actin assembly.