Low-density lipoprotein receptor-related protein-1 (LRP1) mediates autophagy and apoptosis caused by Helicobacter pylori VacA

Kinnosuke Yahiro, Mamoru Satoh, Masayuki Nakano, Junzo Hisatsune, Hajime Isomoto, Jan Sap, Hidekazu Suzuki, Fumio Nomura, Masatoshi Noda, Joel Moss, Toshiya Hirayama

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Abstract

In Helicobacter pylori infection, vacuolating cytotoxin (VacA)-induced mitochondrial damage leading to apoptosis is believed to be a major cause of cell death. It has also been proposed that VacA-induced autophagy serves as a host mechanism to limit toxin-induced cellular damage. Apoptosis and autophagy are two dynamic and opposing processes that must be balanced to regulate cell death and survival. Here we identify the low-density lipoprotein receptor-related protein-1 (LRP1) as the VacA receptor for toxin-induced autophagy in the gastric epithelial cell line AZ-521, and show that VacA internalization through binding to LRP1 regulates the autophagic process including generation of LC3-II from LC3-I, which is involved in formation of autophagosomes and autolysosomes. Knockdown of LRP1 and Atg5 inhibited generation of LC3-II as well as cleavage of PARP, a marker of apoptosis, in response to VacA, whereas caspase inhibitor, benzyloxycarbonyl-VAD- fluoromethylketone (Z-VAD-fmk), and necroptosis inhibitor, Necrostatin-1, did not inhibit VacA-induced autophagy, suggesting that VacA-induced autophagy via LRP1 binding precedes apoptosis. Other VacA receptors such as RPTPα, RPTPβ, and fibronectin did not affect VacA-induced autophagy or apoptosis. Therefore, we propose that the cell surface receptor, LRP1, mediates VacA-induced autophagy and apoptosis.

Original languageEnglish
Pages (from-to)31104-31115
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number37
DOIs
Publication statusPublished - 2012 Sep 7

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Yahiro, K., Satoh, M., Nakano, M., Hisatsune, J., Isomoto, H., Sap, J., Suzuki, H., Nomura, F., Noda, M., Moss, J., & Hirayama, T. (2012). Low-density lipoprotein receptor-related protein-1 (LRP1) mediates autophagy and apoptosis caused by Helicobacter pylori VacA. Journal of Biological Chemistry, 287(37), 31104-31115. https://doi.org/10.1074/jbc.M112.387498