{"doi":"10.1101/2021.07.02.450318","title":"Plakoglobin and HMGB1 mediate intestinal epithelial cell apoptosis induced by <i>Clostridioides difficile</i> TcdB","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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":225684,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9666,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":828406,"name":"Wei Xu","orcid":"0000-0002-6370-7930","position":1,"is_corresponding":false},{"id":828822,"name":"Yutian Ren","orcid":null,"position":2,"is_corresponding":false},{"id":828407,"name":"Hung‐Chi Cheung","orcid":"0000-0002-0747-8686","position":3,"is_corresponding":false},{"id":828408,"name":"Panpan Huang","orcid":"0000-0003-2303-7036","position":4,"is_corresponding":false},{"id":828409,"name":"Guneet Kaur","orcid":"0000-0003-2293-9708","position":5,"is_corresponding":false},{"id":828410,"name":"Chih‐Jung Kuo","orcid":"0000-0002-4988-5124","position":6,"is_corresponding":false},{"id":713170,"name":"Sean P. McDonough","orcid":"0000-0002-0318-0591","position":7,"is_corresponding":false},{"id":828411,"name":"Susan L. Fubini","orcid":"0000-0002-0943-0942","position":8,"is_corresponding":false},{"id":237944,"name":"Steven M. Lipkin","orcid":"0000-0002-0603-9139","position":9,"is_corresponding":false},{"id":490711,"name":"Xin Deng","orcid":"0000-0003-1580-0089","position":10,"is_corresponding":false},{"id":828412,"name":"Yung‐Fu Chang","orcid":"0000-0001-8902-3089","position":11,"is_corresponding":false},{"id":828413,"name":"Linfeng Huang","orcid":"0000-0002-0322-4929","position":12,"is_corresponding":false},{"id":828405,"name":"Yingxue Li","orcid":"0000-0002-4317-9608","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:30.292454Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}