Plakoglobin and High-Mobility Group Box 1 Mediate Intestinal Epithelial Cell Apoptosis Induced by Clostridioides difficile TcdB

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4 Scopus Citations
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Author(s)

  • Panpan Huang
  • Guneet Kaur
  • Chih-Jung Kuo
  • Sean P. McDonough
  • Susan L. Fubini
  • Stephen M. Lipkin
  • Yung-Fu Chang
  • Linfeng Huang

Detail(s)

Original languageEnglish
Number of pages18
Journal / PublicationmBio
Volume13
Issue number5
Online published31 Aug 2022
Publication statusPublished - Oct 2022

Link(s)

Abstract

Clostridioides difficile infection (CDI) is the leading cause of antibiotic-associated intestinal disease, resulting in severe diarrhea and fatal pseudomembranous colitis. TcdB, one of the essential virulence factors secreted by this bacterium, induces host cell apoptosis through a poorly understood mechanism. Here, we performed an RNA interference (RNAi) screen customized to Caco-2 cells, a cell line model of the intestinal epithelium, to discover host factors involved in TcdB-induced apoptosis. We identified plakoglobin, also known as junction plakoglobin (JUP) or γ-catenin, a member of the catenin family, as a novel host factor and a previously known cell death-related chromatin factor, high-mobility group box 1 (HMGB1). Disruption of those host factors by RNAi and CRISPR resulted in resistance of cells to TcdB-mediated and mitochondrion-dependent apoptosis. JUP was redistributed from adherens junctions to the mitochondria and colocalized with the antiapoptotic factor Bcl-XL. JUP proteins could permeabilize the mitochondrial membrane, resulting in the release of cytochrome c. Our results reveal a novel role of JUP in targeting the mitochondria to promote the mitochondrial apoptotic pathway. Treatment with glycyrrhizin, an HMGB1 inhibitor, resulted in significantly increased resistance to TcdB-induced epithelial damage in cultured cells and a mouse ligated colon loop model. These findings demonstrate the critical roles of JUP and HMGB1 in TcdB-induced epithelial cell apoptosis. © 2022 Li et al.

Research Area(s)

  • C. difficile, TcdB, apoptosis, JUP, HMGB1, RNAi screen, TOXIN-B, BARRIER FUNCTION, PROTEIN, INFECTION, INFLAMMATION, IDENTIFICATION, MITOCHONDRIA, RECEPTOR, STRAIN, TARGET

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