ZFP36 promotes VDR mRNA degradation to facilitate cell death in oral and colonic epithelial cells

Xiangyu Wang,Jie Du,Yong Cao,Wang Liao,Ran Li,Bin Zhao,Fang Zhang,Xuejun Ge

doi:10.1186/s12964-021-00765-4

Abstract

BackgroundVitamin D receptor (VDR) plays a vital protective role in oral and colonic epithelial cells. Albeit we know that VDR expression is reduced in the mucosal epithelial layers of autoimmune diseases, the mechanism by which VDR is decreased remains elusive.MethodsVDR and zinc finger protein 36 (ZFP36) levels in human samples and cell lines were detected by real-time PCR, western blot and immunostaining. Luciferase report assay was used to test cis-elements in VDR gene promoter, real-time PCR was applied to measure mRNA decay and western blot was performed to evaluate protein degradation. RNA affinity chromatography assay was used to test protein-mRNA interaction. Co-immunoprecipitation was used to detect protein–protein interaction. The role of ZFP36 in AU-rich elements (AREs) in the 3′ untranslated region (UTR) of VDR mRNA was also measured by luciferase report assay.ResultsWe identify ZFP36 can bind with the AREs in the 3’UTR of VDR mRNA, leading to mRNA degradation in oral and colonic epithelial cells under inflammatory circumstance. Either ZFP36 protein or AREs of VDR mRNA mutation abolishes this protein-mRNA binding process. After the key amino acid’s mutation, ZFP36 fails to decrease VDR mRNA expression. We also find that VDR physically binds with Y box-binding protein 1 (YBX-1) to block YBX-1’s nuclear translocation and ameliorate cell death in the presence of inflammation.ConclusionThese findings provide insights into the cause of VDR decrease in oral and colonic epithelial cells under inflammatory condition and explain how VDR maintains cell viability in these cells.6BzbZFy5QCY-oJ2EBzKUxNVideo abstract

Highlights

Vitamin D receptor (VDR) plays a vital protective role in oral and colonic epithelial cells
VDR expression is downregulated in the oral and colonic epithelial cells under inflammatory condition Our previous studies have claimed that VDR functions as a protective mediator in the diseased tissues derived from oral lichen planus (OLP) and inflammatory bowel disease (IBD) [8, 14, 27]
In accordant with these data in vitro, both mRNA and protein levels of VDR exhibited reductions in the human diseased samples compared to healthy controls (Fig. 1e, f )

Summary

Introduction

Vitamin D receptor (VDR) plays a vital protective role in oral and colonic epithelial cells. Aberrant apoptosis of oral or colonic epithelial cells is regarded as a major pathogenic underpinning resulting in increased epithelial layer permeability and mucosal. Excessive mucosal epithelial cells apoptosis has been indicated in the diseased tissues from patients with oral lichen planus (OLP) and inflammatory bowel disease (IBD), the two typical inflammatory diseases in oral and colonic mucosae [6,7,8]. Other cell death-associated molecular programmes such as pyroptosis, ferroptosis and necroptosis all contribute to the death of colonic epithelial cells [9]. If these pathways are uncontrollably induced, they may become pathological and lead to inflammatory diseases [9]

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