LDL receptor-mediated endocytosis of Escherichia coli α- hemolysin mediates renal epithelial toxicity

• 成果类型: Article
• 署名作者: Kuhn, Hunter W.; Smither, Madeleine R.; Jin, Rachel J.; Collins, Christina A.; Ma, Hongming; Sina, Jason; Gaut, Joseph P.; Diamond, Michael S.; Hunstad, David A.
• 署名单位: Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL); Washington University (WUSTL)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12679
• DOI: 10.1073/pnas.2505482122
• 发表日期: 2025-06-17
• 关键词: urinary-tract-infection; pore-forming toxin; familial hypercholesterolemia; virulence factors; rtx-toxins; cholesterol; proteins; expression; antibodies; survival

摘要

The alpha- hemolysin (HlyA) of uropathogenic Escherichia coli (UPEC) is a pore-forming toxin (PFT) that is thought to function by disrupting the host cell plasma membrane. Although CD18 (LFA-1) has been implicated as a receptor on myeloid cells, the mechanisms underlying HlyA cytotoxicity to epithelial cells are poorly defined. Here, we show that HlyA secretion by UPEC markedly intensifies renal tubular epithelial injury in a murine model of ascending pyelonephritis. A CRISPR-Cas9 loss-of-function screen in renal collecting duct cells revealed an unexpected requirement for clathrin-mediated endocytosis in HlyA-induced cytotoxicity. Following internalization, HlyA triggered lysosomal permeabilization, resulting in protease leakage, cytoplasmic acidification, and mitochondrial impairment, culminating in rapid epithelial cell death-a pathway distinct from canonical membrane-disrupting mechanisms of other PFTs. Moreover, we identify the low-density lipoprotein receptor (LDLR) as a critical epithelial receptor for HlyA; genetic ablation or competitive inhibition of the HlyA-LDLR interaction fully abrogated cytotoxicity. Our findings detail a paradigm for HlyA function in which epithelial toxicity relies on LDLR-mediated endocytic uptake rather than plasma membrane poration. These mechanistic insights illuminate potential therapeutic strategies to attenuate HlyA-mediated tissue damage during UPEC infections.