<p>Oligonucleotide primers used in this study.</p>

Lysosomes regulate cuticle collagen turnover, yet how neuronal signaling modulates epidermal lysosomal function and collagen organization during infection remains unclear. Using <i>Pseudomonas aeruginosa</i> PA14-<i>Caenorhabditis elegans</i> infection model, we demonstrate that pathogen-induced neuronal signaling disrupts epidermal lysosomal activity and collagen remodeling.

PA14 infection triggers neurons to secrete NSIF-1 (Neuronal Secreted Immune Factor 1), which translocates to the epidermis and impairs lysosomal acidification, maturation, and degradation by suppressing the transcription factor ELT-3. This disruption leads to disorganized collagen structure, compromising cuticle integrity and host resistance. Genetic mutation of <i>nsif-1</i> restores lysosomal function, enhances collagen density, and improves survival, while neuron-specific <i>nsif-1</i> knockdown confirms its neuronal origin.