Epithelial CRL4 DCAF2 is critical for maintaining intestinal homeostasis by regulating the proliferation and repair of intestinal epithelial cells-Reference-Cited by-同舟云学术

Epithelial CRL4 DCAF2 is critical for maintaining intestinal homeostasis by regulating the proliferation and repair of intestinal epithelial cells

Published:2022-12-09 Issue: Volume: Page:
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Author:

Zhang Yu¹,Wang Chaohui²,lexi Wu¹,Bai Chenhao¹,Huang Kaituo¹,Yao Lingya¹,Zhang Zhou¹,Ye Lingna¹,Liu Rongbei¹,Ge Xiaolong¹,Xu Mengque¹,Xiao Peng¹,Zhao Yuan¹,Cao Qian¹

Affiliation:

1. Zhejiang University

2. Taizhou Central Hospital

Abstract

Abstract Background & Aims: Inflammatory bowel disease (IBD) is becoming more and more popular in the whole wide world. Intestinal epithelial barrier dysfunction is an important step to IBD while the mechanisms are not fully understood. This study aimed to clarify the function of CRL4DCAF2, an E3 ligase, in maintaining intestinal homeostasis. Methods: Expression of CRL4DCAF2 was evaluated in colon samples taken from IBD patients and healthy people. CRL4DCAF2 conditional knockdown in intestinal epithelial cells (IECs) mice (DCAF2EKD) were constructed. DCAF2EKD and their littermate control (DCAF2EWT) were treated with dextran sodium sulfate (DSS) to induce acute colitis. Transcriptome analysis was performed on inflamed colon samples taken from the mice. Cell cycle molecules were evaluated by real-time PCR while tight junction proteins and apoptosis proteins were examined by immunofluorescence and western blot. Results: CRL4DCAF2 was significantly decreased in the inflamed IBD epithelium, and low expression of CRL4DCAF2 associated with high recurrence risk. Mouse with DCAF2 specific knockout in IECs suffer from embryonic death. Multiple genes involved in cell proliferation, immune response and gap junction were differentially expressed in inflamed colon from DCAF2EKD compared to DCAF2EWT. Among these, in mice, conditional downregulation of CRL4DCAF2 in the intestinal epithelium induced primarily epithelial damage, increased intestinal permeability and diminished tight junction proteins expression. From in vivo and in vitro cell transfection experiments, we found CRL4DCAF2 promoted the proliferation by promoting p21 ubiquitination and degradation thus releasing its inhibition on G2/M cell cycle. In addition, CRL4DCAF2 can also inhibit IEC apoptosis and advance cell autophagy. Conclusions: CRL4DCAF2 downregulation in IECs promotes intestinal barrier dysfunction postpones IECs renewal thus made it more Susceptible to inflammation.

Publisher

Research Square Platform LLC

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