Regenerating islet-derived 3A (REG3A) is thought to recognize and kill its bacterial targets in two distinct steps (Mukherjee S et al. 2014). First, REG3A is secreted from epithelial cells as a soluble monomer that recognizes Gram-positive bacteria by binding to peptidoglycan carbohydrate via an EPN motif located in the long loop region (Lehotzky RE et al. 2010). Second, REG3A kills bacteria by oligomerizing in the bacterial membrane to form a hexameric membrane-penetrating pore that is predicted to induce uncontrolled ion efflux with subsequent osmotic lysis (Mukherjee S et al. 2014). The inhibitory N-terminus of REG3A propeptide hinders lipid binding and consequently suppresses pore formation until it is removed by trypsin after secretion into the intestinal lumen (Mukherjee S et al. 2009; 2014).