Plakoglobin and HMGB1 mediate intestinal epithelial cell apoptosis induced by Clostridioides difficile TcdB

Yingxue Li, Wei Xu, Yutian Ren, Hung-Chi Cheung, Panpan Huang, Guneet Kaur, Chih-Jung Kuo, Sean P. McDonough, Susan L. Fubini, Stephen M. Lipkin, Xin Deng, Yung-Fu Chang, Linfeng Huang
2021 · doi:10.1101/2021.07.02.450318
preprint OA: closed
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Abstract

Summary 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 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 mitochondria-dependent apoptosis. JUP was redistributed from adherens junctions to the mitochondria and colocalized with Bcl-X L after stimulation by TcdB, suggesting a role of JUP in cell death signaling through mitochondria. 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.

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