Hui-Chen Hsieh, Yi-Lin Cheng, Chyuan-Chuan Wu, Chee Kit Joshua Luk, Yi-Hsiu Weng, Tzu-Hsuan Chiu, Shao-Wen Chang, Ting-Wei Chang, Yan-Ning Gu, Jhen-Wei Ruan, Tzer-Min Lee, Shuying Wang, Po-Lin Chen, Raffi V Aroian, Chang-Shi Chen
Effector-triggered immunity (ETI) safeguards intestinal epithelial cells (IECs) by surveilling bacterial virulence effectors or the damage they cause, such as pore-forming toxins (PFTs) that breach plasma membrane integrity (PMI). However, how metazoan ETI regulators guard IEC homeostasis compromised by PFT in vivo remains elusive. Moreover, while the molecular architectures of ETI are well-defined in plants, functionally analogous systems in animals are only beginning to emerge. Here, we unveil a conserved ETI guard system - the intestinal ETI regulator methyl-HLH-30/TFEB upregulates a novel intrinsic cellular defense (INCED) orchestrator Y54G11A.4/TTC38 - in Caenorhabditis elegans and human IECs. This conserved ETI system coordinates the restoration of PMI, microvilli architecture, and nutrient absorption concurrently by promoting phase condensation of the PTRN-1/CAMSAP-dependent guard program through an HSPA/HSP70-HSP90 chaperone system. Together, our findings reveal an intestinal ETI guard system that couples PFT-damage sensing to comprehensive epithelial recuperation, underscoring its physiological relevance for mucosal homeostasis across metazoans.