Intestinal ETI-regulator methyl-HLH-30/TFEB orchestrates conserved and holistic recuperations for bacterial pore-forming toxin-induced damage

Effector-triggered immunity (ETI) safeguards intestinal epithelial cells (IECs) by surveilling bacterial virulence effectors and effector-induced cellular stress, such as plasma membrane damage induced by pore-forming toxins (PFTs). However, the knowledge about ETI regulators in maintaining IEC homeostasis in vivo remained elusive. Plasma membrane integrity (PMI) and microvilli morphology are essential for barrier function and nutrient absorption of IECs; thus, PFT effectors compromise these structures are detrimental to animal survival. Here, we identify a conserved ETI program in IECs of C. elegans and humans. The intestinal ETI regulator methyl-HLH-30/TFEB upregulates a novel intrinsic cellular defense (INCED) orchestrator Y54G11A.4/TTC38. This pathway coordinates restorations of PMI, microvilli architecture, and nutrient uptake by promoting phase condensation of the microtubule organizer PTRN-1/CAMSAP through an HSP70/HSP90 chaperone system. Our findings reveal an ETI program integrating host defense with holistic epithelial repair and delineating a novel and conserved ETI-induced INCED program for mucosal homeostasis across metazoans.