Fig. 1.

FRMPD2 localizes NOD2 to the basolateral membrane in polarized intestinal epithelial cells and dictates spatial specificity to NOD2 signaling. (A) Under normal conditions in the gut, NOD2 localizes to the basolateral membrane through interactions with FRMPD2 and is nonresponsive to commensal bacteria present on apical surfaces through an interaction with ERBB2IP. (B) When injury or pathogenic infection occurs, cells are exposed to bacteria (MDP) basolaterally. Membrane-associated NOD2 senses MDP and is released from ERBB2IP repression, which results in recruitment of RIP2 to the membrane, initiation of signaling through NFκB, and stimulation of a proinflammatory and antibacterial response. (C) In a disease context [i.e., FRMPD2 expression is decreased by inflammatory signals (Left) or a Crohn disease-associated NOD2 variant (L1007fs) is expressed], NOD2 is mislocalized and is unable to respond effectively and clear the bacterial infection.