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

Dong Fu,Peng Li,Zhibao Lv,Qingfeng Sheng

doi:10.18632/aging.102320

Abstract

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

Highlights

Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergencies in premature infants, and is associated with significant morbidity and mortality [1]
We have presented a large body of evidence that β-arrestin-2 inhibits BiP in intestinal epithelial cells (IECs), promoting the release of BIK and stimulating Endoplasmic reticulum (ER)-stressinduced apoptosis
All these results indicated that β-arrestin-2 promotes ER-stress-induced cell death by inhibiting BiP

Summary

INTRODUCTION

Necrotizing enterocolitis (NEC) is one of the most common gastrointestinal emergencies in premature infants, and is associated with significant morbidity and mortality [1]. Endoplasmic reticulum (ER) stress-induced apoptosis of intestinal epithelial cells (IECs) has come to be recognized as an important promoter of most gastrointestinal diseases [2]. The genetic knockdown of proteins involved in the unfolded protein response has been reported to cause Paneth cell dysfunction or apoptosis, and to increase the susceptibility of mice to dextran sodium sulfate (DSS)induced colitis and spontaneous intestinal inflammation [5]. We hypothesized that β-arrestin-2 induces pathological ER stress by binding to BiP, increasing BIK release, stimulating apoptosis and promoting the development of NEC. The susceptibility of premature infants to NEC may be partly ascribed to their higher baseline intestinal β-arrestin-2 expression

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS