Paneth cells are a highly-specialized secretory cells at the bottom of the crypt in small intestine.Paneth cells play an essential role in maintaining intestinal homeostasis by secreting large amount of microbicidal peptides into gut lumen.Like many professional secretory cells, Paneth cells secrete microbicidal peptides through dense-core vesicles (DCVs).Currently, the mechanisms governing DCV cargo sorting are highly controversial.Here, we present evidence showing Dardarin, a highly interesting gene implicated in both Parkinsons disease and inflammatory bowel disease, plays an indispensable role in lysozyme sorting in Paneth cells.Dardarin deficient Paneth cells lack lysozyme in DCVs, which renders the mice more susceptible to intestinal infection.Our mechanistic investigation has shown Dardarin forms a platform on the surface of DCVs to recruit important components governing cargo sorting.Dardarin deficiency leads to the failure of such recruitment.Our results not only illustrate the important physiological function of Dardarin, but also could shed light on the general mechanism governing DCV cargo sorting.