Mechanotransduction activates RhoA in the neighbors of apoptotic epithelial cells to engage apical extrusion

• Published in: Current biology Vol. 31; no. 6; pp. 1326 - 1336.e5
• Main Authors: Duszyc, Kinga, Gomez, Guillermo A., Lagendijk, Anne K., Yau, Mei-Kwan, Nanavati, Bageshri Naimish, Gliddon, Briony L., Hall, Thomas E., Verma, Suzie, Hogan, Benjamin M., Pitson, Stuart M., Fairlie, David P., Parton, Robert G., Yap, Alpha S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 22.03.2021
• Subjects: Animals; apical extrusion; Apoptosis; apoptotic elimination; Cadherins - genetics; epithelial apoptosis; Epithelial Cells - cytology; Lysophospholipids; mechanotransduction; Mechanotransduction, Cellular; RhoA; rhoA GTP-Binding Protein - physiology; Sphingosine - analogs & derivatives; Zebrafish; apoptotic elimination; apical extrusion; epithelial apoptosis; mechanotransduction; RhoA
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2021.01.003

Epithelia must eliminate apoptotic cells to preserve tissue barriers and prevent inflammation.1 Several different mechanisms exist for apoptotic clearance, including efferocytosis2,3 and apical extrusion.4,5 We found that extrusion was the first-line response to apoptosis in cultured monolayers and in zebrafish epidermis. During extrusion, the apoptotic cell elicited active lamellipodial protrusions and assembly of a contractile extrusion ring in its neighbors. Depleting E-cadherin compromised both the contractile ring and extrusion, implying that a cadherin-dependent pathway allows apoptotic cells to engage their neighbors for extrusion. We identify RhoA as the cadherin-dependent signal in the neighbor cells and show that it is activated in response to contractile tension from the apoptotic cell. This mechanical stimulus is conveyed by a myosin-VI-dependent mechanotransduction pathway that is necessary both for extrusion and to preserve the epithelial barrier when apoptosis was stimulated. Earlier studies suggested that release of sphingosine-1-phosphate (S1P) from apoptotic cells might define where RhoA was activated. However, we found that, although S1P is necessary for extrusion, its contribution does not require a localized source of S1P in the epithelium. We therefore propose a unified view of how RhoA is stimulated to engage neighbor cells for apoptotic extrusion. Here, tension-sensitive mechanotransduction is the proximate mechanism that activates RhoA specifically in the immediate neighbors of apoptotic cells, but this also must be primed by S1P in the tissue environment. Together, these elements provide a coincidence detection system that confers robustness on the extrusion response. [Display omitted] •Contractility in apoptotic epithelial cells stimulates RhoA in their neighbors•Apoptotic contractility is detected by E-cadherin-based mechanotransduction•Mechanotransduction requires priming by sphingosine-1-phosphate (S1P) signaling•Mechanotransduction and S1P signaling thus collaborate for apoptotic extrusion Epithelia eliminate apoptotic cells by apical extrusion. Duszyc et al. show that this reflects an E-cadherin-based mechanotransduction pathway that is primed by S1P. Mechanotransduction activates RhoA in the neighbor cells in response to contractility in the apoptotic cells to drive extrusion and preserve tissue integrity.