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The immune system acts as a shield against harmful microbes and requires exquisite control of the activation and resolution of multiple signaling pathways. Tight regulation of these processes is required not only to produce an effective response, but also to maintain immune homeostasis and prevent autoinflammatory disease. In the intestine, this process is further complicated by the residence of a beneficial community of microbes. One major question is how the immune system determines “friend from foe,” restricting antimicrobial responses to the intestinal microbiota but retaining protective antimicrobial responses against pathogens. Answering this question is critical to uncovering mechanisms that go awry in autoinflammatory disease. In PNAS, Lipinsky et al. (1) provide mechanistic insights into how polarized intestinal epithelial cells restrict antibacterial responses to the basolateral compartment through directing the subcellular localization the bacterial sensor NOD2 (nucleotide-binding oligomerization domain-2). NOD2 is a member of the phylogenetically conserved NOD-like receptor family, which recognizes microbe-associated molecular patterns (i.e., bacterial peptidoglycan, flagellin, and so forth) and danger-associated molecular patterns (i.e., reactive oxygen species, ATP, and others.) in the cell cytosol (2). The NOD2 protein is primarily expressed in granulocytes, antigen-presenting cells, Paneth cells, and intestinal epithelial cells. NOD2 is activated by the muramyl dipeptide (MDP) component of the peptidoglycan cell wall present in most bacteria (3, 4). Like other NOD-like receptors, NOD2 forms a dynamic macromolecular platform with multiple proteins upon activation, which dictates cellular responses to bacteria. These responses include the production of cytokines, chemokines, and antimicrobial peptides, activation of autophagy, and stimulation of antigen presentation. The critical role of NOD2 in immune homeostasis is demonstrated by the association of both gain-of-function and loss-of-function NOD2 genetic variants with chronic inflammatory diseases, such as Crohn disease and Blau syndrome. Because of its pivotal role in maintaining gut homeostasis, it is critical to understand …

FRMBP2 directs NOD2 to the membrane