β-arrestin-2 enhances intestinal epithelial apoptosis in necrotizing enterocolitis.

Apoptosis among intestinal epithelial cells contributes to necrotizing enterocolitis (NEC), a severe intestinal disease that particularly affects premature infants. beta-arrestin-2, an important regulator of G-protein-coupled receptors, is expressed in intestinal epithelial cells, where its activation promotes apoptosis. We found that beta-arrestin-2 was overexpressed in both human and murine NEC samples. beta-arrestin-2-deficient mice were protected from endoplasmic reticulum stress and NEC development. The endoplasmic reticulum-resident chaperone BiP was found to promote intestinal epithelial cell survival. Pretreatment of intestinal epithelial cells or mice with the BiP inhibitor HA15 increased cell apoptosis and promoted NEC development. beta-arrestin-2 bound to BiP and promoted its polyubiquitination and degradation, thereby facilitating the release of the proapoptotic molecule BIK from BiP. Silencing beta-arrestin-2 downregulated apoptosis by increasing BiP levels, which suppressed endoplasmic reticulum stress. This study suggests that beta-arrestin-2 induces NEC development by inhibiting BiP, thereby triggering apoptosis in response to endoplasmic reticulum stress. Thus, novel therapeutic strategies to inhibit beta-arrestin-2 may enhance the treatment of NEC.