Department of Molecular and Cellular Medicine, Texas A&M University, College of Medicine, Bryan, Texas, United States of America.
PLoS Biol. 2022 May 6;20(5):e3001635. doi: 10.1371/journal.pbio.3001635. eCollection 2022 May.
Balancing cellular demise and survival constitutes a key feature of resilience mechanisms that underlie the control of epithelial tissue damage. These resilience mechanisms often limit the burden of adaptive cellular stress responses to internal or external threats. We recently identified Diedel, a secreted protein/cytokine, as a potent antagonist of apoptosis-induced regulated cell death in the Drosophila intestinal midgut epithelium during aging. Here, we show that Diedel is a ligand for RGD-binding Integrins and is thus required for maintaining midgut epithelial cell attachment to the extracellular matrix (ECM)-derived basement membrane. Exploiting this function of Diedel, we uncovered a resilience mechanism of epithelial tissues, mediated by Integrin-ECM interactions, which shapes cell death spreading through the regulation of cell detachment and thus cell survival. Moreover, we found that resilient epithelial cells, enriched for Diedel-Integrin-ECM interactions, are characterized by membrane association of Catalase, thus preserving extracellular reactive oxygen species (ROS) balance to maintain epithelial integrity. Intracellular Catalase can relocalize to the extracellular membrane to limit cell death spreading and repair Integrin-ECM interactions induced by the amplification of extracellular ROS, which is a critical adaptive stress response. Membrane-associated Catalase, synergized with Integrin-ECM interactions, likely constitutes a resilience mechanism that helps balance cellular demise and survival within epithelial tissues.
平衡细胞凋亡和存活是弹性机制的一个关键特征，这些机制是控制上皮组织损伤的基础。这些弹性机制通常限制了适应性细胞应激反应对内源或外源威胁的负担。我们最近发现，分泌蛋白/细胞因子 Diedel 是果蝇肠道中皮细胞衰老过程中凋亡诱导的细胞程序性死亡的有效拮抗剂。在这里，我们表明 Diedel 是 RGD 结合整联蛋白的配体，因此是维持中皮细胞与细胞外基质（ECM）衍生的基底膜附着所必需的。利用 Diedel 的这一功能，我们揭示了上皮组织的一种弹性机制，该机制由整合素-ECM 相互作用介导，通过调节细胞脱离来塑造细胞死亡的扩散，从而维持细胞存活。此外，我们发现富含 Diedel-整合素-ECM 相互作用的弹性上皮细胞的特征是 Catalase 与膜的关联，从而保持细胞外活性氧（ROS）平衡，以维持上皮完整性。细胞内 Catalase 可以重新定位于细胞外膜，以限制细胞死亡的扩散，并修复由细胞外 ROS 扩增引起的整合素-ECM 相互作用，这是一种关键的适应性应激反应。与整合素-ECM 相互作用协同作用的膜相关 Catalase，可能构成一种弹性机制，有助于平衡上皮组织内的细胞凋亡和存活。
