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Epithelial homeostasis can be critically influenced by how cells respond to mechanical forces, both local changes in force balance between cells and altered tissue-level forces. 1 Coupling of specialized cell-cell adhesions to their cytoskeletons provides epithelia with diverse strategies to respond to mechanical stresses. 2 , 3 , 4 Desmosomes confer tissue resilience when their associated intermediate filaments (IFs) 2 , 3 stiffen in response to strain, 5 , 6 , 7 , 8 , 9 , 10 , 11 while mechanotransduction associated with the E-cadherin apparatus 12 , 13 at adherens junctions (AJs) actively modulates actomyosin by RhoA signaling. Although desmosomes and AJs make complementary contributions to mechanical homeostasis in epithelia, 6 , 8 there is increasing evidence to suggest that these cytoskeletal-adhesion systems can interact functionally and biochemically. 8 , 14 , 15 , 16 , 17 , 18 , 19 , 20 We now report that the desmosome-IF system integrated by desmoplakin (DP) facilitates active tension sensing at AJs for epithelial homeostasis. DP function is necessary for mechanosensitive RhoA signaling at AJs to be activated when tension was applied to epithelial monolayers. This effect required DP to anchor IFs to desmosomes and recruit the dystonin (DST) cytolinker to apical junctions. DP RNAi reduced the mechanical load that was applied to the cadherin complex by increased monolayer tension. Consistent with reduced mechanical signal strength, DP RNAi compromised assembly of the Myosin VI-E-cadherin mechanosensor that activates RhoA. The integrated DP-IF system therefore supports AJ mechanotransduction by enhancing the mechanical load of tissue tension that is transmitted to E-cadherin. This crosstalk was necessary for efficient elimination of apoptotic epithelial cells by apical extrusion, demonstrating its contribution to epithelial homeostasis., Competing Interests: Declaration of interests A.S.Y. is a member of the Current Biology Advisory Board., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Apical extrusion is a tissue-intrinsic process that allows epithelia to eliminate unfit or surplus cells. This is exemplified by the early extrusion of apoptotic cells, which is critical to maintain the epithelial barrier and prevent inflammation. Apoptotic extrusion is an active mechanical process, which involves mechanotransduction between apoptotic cells and their neighbors, as well as local changes in tissue mechanics. Here we report that the preexisting mechanical tension at adherens junctions (AJs) conditions the efficacy of apoptotic extrusion. Specifically, increasing baseline mechanical tension by overexpression of a phosphomimetic Myosin II regulatory light chain (MRLC) compromises apoptotic extrusion. This occurs when tension is increased in either the apoptotic cell or its surrounding epithelium. Further, we find that the proinflammatory cytokine, TNFα, stimulates Myosin II and increases baseline AJ tension to disrupt apical extrusion, causing apoptotic cells to be retained in monolayers. Importantly, reversal of mechanical tension with an inhibitory MRLC mutant or tropomyosin inhibitors is sufficient to restore apoptotic extrusion in TNFα-treated monolayers. Together, these findings demonstrate that baseline levels of tissue tension are important determinants of apoptotic extrusion, which can potentially be coopted by pathogenetic factors to disrupt the homeostatic response of epithelia to apoptosis.

Epithelia must eliminate apoptotic cells to preserve tissue barriers and prevent inflammation. 1 Several different mechanisms exist for apoptotic clearance, including efferocytosis 2 , 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cell extrusion is a striking morphological event found in epithelia and endothelia. It is distinguished by two symmetry-breaking events: a loss of planar symmetry, as cells are extruded in either apical or basal directions; and loss of mechanochemical homogeneity within monolayers, as cells that are fated to be extruded become biochemically and mechanically distinct from their neighbors. Cell extrusion is elicited by many diverse events, from apoptosis to the expression of transforming oncogenes. Does the morphological outcome of extrusion reflect cellular processes that are common to these diverse biological phenomena? To address this question, in this review we compare the progress that has been made in understanding how extrusion is elicited by epithelial apoptosis and cell transformation.