title: Low-density lipoprotein receptor-related protein-1 (LRP1) mediates autophagy and apoptosis caused by Helicobacter pylori VacA.
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.
authors: Department of Molecular Infectiology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan.
authors: Kinnosuke
authors: K
authors: Yahiro
authors: Mamoru
authors: M
authors: Satoh
authors: Masayuki
authors: M
authors: Nakano
authors: Junzo
authors: J
authors: Hisatsune
authors: Hajime
authors: H
authors: Isomoto
authors: Jan
authors: J
authors: Sap
authors: Hidekazu
authors: H
authors: Suzuki
authors: Fumio
authors: F
authors: Nomura
authors: Masatoshi
authors: M
authors: Noda
authors: Joel
authors: J
authors: Moss
authors: Toshiya
authors: T
authors: Hirayama
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D016481:Helicobacter Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016480:Helicobacter pylori / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics / Q000378:metabolism; D013270:Stomach / Q000382:microbiology / Q000473:pathology
chemical_list: C502778:ATG5 protein, human; D000590:Amino Acid Chloromethyl Ketones; D000071187:Autophagy-Related Protein 5; D001426:Bacterial Proteins; D015853:Cysteine Proteinase Inhibitors; D005353:Fibronectins; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008869:Microtubule-Associated Proteins; C074689:VacA protein, Helicobacter pylori; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D011065:Poly(ADP-ribose) Polymerases; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5