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

Dong Fu1, Peng Li1, Qingfeng Sheng1

  • 1Department of General Surgery, Children's Hospital of Shanghai, School of Medicine, Shanghai Jiao Tong University, Shanghai 200000, China.

Aging
|October 16, 2019
PubMed

Insights

Necrotizing enterocolitis (NEC) in premature infants involves intestinal cell apoptosis. Inhibiting beta-arrestin-2 protects against NEC by preventing BiP degradation and reducing endoplasmic reticulum stress.

Area of Science:

  • Gastroenterology
  • Cell Biology
  • Neonatal Medicine

Background:

  • Apoptosis of intestinal epithelial cells is a key factor in necrotizing enterocolitis (NEC), a serious condition affecting premature infants.
  • Beta-arrestin-2 (a regulator of G-protein-coupled receptors) promotes apoptosis in intestinal epithelial cells.
  • Overexpression of beta-arrestin-2 is observed in human and murine NEC samples.

Purpose of the Study:

  • To investigate the role of beta-arrestin-2 in the development of NEC.
  • To elucidate the mechanism by which beta-arrestin-2 influences endoplasmic reticulum stress and apoptosis in intestinal epithelial cells.
  • To explore the therapeutic potential of targeting beta-arrestin-2 for NEC treatment.

Main Methods:

  • Comparative analysis of beta-arrestin-2 expression in human and murine NEC samples versus controls.
  • Assessment of NEC development and endoplasmic reticulum stress in beta-arrestin-2-deficient mice.
  • In vitro studies using intestinal epithelial cells treated with BiP inhibitor HA15.
  • Investigation of the interaction between beta-arrestin-2 and BiP, including polyubiquitination and degradation pathways.
  • Gene silencing of beta-arrestin-2 to evaluate its impact on apoptosis and BiP levels.

Main Results:

  • Beta-arrestin-2-deficient mice showed protection against endoplasmic reticulum stress and NEC development.
  • Inhibition of BiP (an endoplasmic reticulum-resident chaperone promoting cell survival) increased apoptosis and promoted NEC.
  • Beta-arrestin-2 directly binds to BiP, promoting its polyubiquitination and degradation, which releases the pro-apoptotic molecule BIK.
  • Silencing beta-arrestin-2 increased BiP levels, reduced apoptosis, and suppressed endoplasmic reticulum stress.

Conclusions:

  • Beta-arrestin-2 induces NEC by inhibiting BiP, leading to apoptosis triggered by endoplasmic reticulum stress.
  • Targeting beta-arrestin-2 presents a potential novel therapeutic strategy for enhancing NEC treatment.

Keywords:
BiPER stressNECapoptosisβ-arrestin-2

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