Activating Transcription Factor 6 Mediates Inflammatory Signals in Intestinal Epithelial Cells Upon Endoplasmic Reticulum Stress.

Gastroenterology
Stephanie T StengelPhilip Rosenstiel

Abstract

Excess and unresolved endoplasmic reticulum (ER) stress in intestinal epithelial cells (IECs) promotes intestinal inflammation. Activating transcription factor 6 (ATF6) is one of the signaling mediators of ER stress. We studied the pathways that regulate ATF6 and its role for inflammation in IECs. We performed an RNA interference screen, using 23,349 unique small interfering RNAs targeting 7783 genes and a luciferase reporter controlled by an ATF6-dependent ERSE (ER stress-response element) promoter, to identify proteins that activate or inhibit the ATF6 signaling pathway in HEK293 cells. To validate the screening results, intestinal epithelial cell lines (Caco-2 cells) were transfected with small interfering RNAs or with a plasmid overexpressing a constitutively active form of ATF6. Caco-2 cells with a CRISPR-mediated disruption of autophagy related 16 like 1 gene (ATG16L1) were used to study the effect of ATF6 on ER stress in autophagy-deficient cells. We also studied intestinal organoids derived from mice that overexpress constitutively active ATF6, from mice with deletion of the autophagy related 16 like 1 or X-Box binding protein 1 gene in IECs (Atg16l1ΔIEC or Xbp1ΔIEC, which both develop spontaneous ileitis), from patient...Continue Reading

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Citations

Dec 17, 2020·Frontiers in Immunology·Sanchez Preethi EugeneJamma Trinath
Jan 8, 2021·Frontiers in Immunology·Florian TranPhilip Seibler
May 1, 2021·Journal of Cell Communication and Signaling·Shijun YuYong Gao
Aug 2, 2021·European Journal of Pharmacology·Jing QuanXiangjian Luo
Oct 9, 2021·The Journal of Clinical Investigation·Kishu RanjanClara Abraham

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