Rip2 Is Required for Nod2-Mediated Lysozyme Sorting in Paneth Cells

Paneth cells play an important role in maintaining intestinal homeostasis by secreting a large number of antimicrobial peptides into the intestinal lumen. In this study, we found that Rip2 is required for lysozyme sorting in Paneth cells in a manner that is dependent on Nod2, LRRK2, and Rab2a. Rip2 deficiency in mouse led to lysosomal degradation of lysozyme in Paneth cells and prevented the recruitment of Rab2a onto dense core vesicles (DCVs). Like Nod2 and LRRK2, Rip2 localizes to DCVs in Paneth cells, and its DCV localization depends on Nod2 and LRRK2. Thus, we delineated a genetic pathway, consisting of Nod2-LRRK2-Rip2-Rab2a, which is required for lysozyme sorting. Taken together, our results indicate that the lysozyme-sorting process in Paneth cells is orchestrated by a number of host factors and highlight the importance of Paneth cell function in intestinal homeostasis.