Being a first-line defense, the epidermis is in constant confrontation against pathological or mechanical insults that disrupt the epidermal architecture. Yet whether and how the immune system of the epidermal cells recognizes its structural damage as a danger signal to activate self-defense remains unclear. Here we use C. elegans epidermis as the model to address this question. The adult C. elegans epidermis is a single-cell-layered tissue with highly organized 3-D architecture. When subjected to skin-penentrating fungal infection or physical injury, it activates innate defense through p38-MAPK and TGF-β signaling cassettes and produces antimicrobial peptides (AMPs) such as nlp-29 and cnc-2. By disrupting each epidermal architectural components seperately, we pinpointed a spatially-restricted group of structures at the apical hemidesmosomes capable of activating epidermal immune defense once damaged. By screening most signaling molecules known to control AMP production, we found that the immune defense against epidermal damage depends on STA-2, but not on any other immune-related signaling pathways known to date. The endogenous STA-2 is mostly associated with apical hemidesmosomes in the healthy epidermis. Disruption of apical hemidesmosomes leads to increased nuclear localization of STA-2 and results in AMP up-regulation. The cooperation between hemidesmosomes and STA-2 enables the epidermis to bypass p38-MAPK and TGF-β signaling pathways and directly turn on immune effector genes when subjected to severe architectural damage by internal or external causes. Together, our findings uncovered a cell-autonomous surveilance program installed within the stable attachment structures of the epidermal cells, and a novel mechanism for the epidermis to detect danger and activate self-defense. These results may also provide mechanistic insights into the pathogenesis of inflammatory diseases involving epidermal damage.
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