title: Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress.
abstract: Pancreatic acinar cells possess very high protein synthetic rates as they need to produce and secrete large amounts of digestive enzymes. Acinar cell damage and dysfunction cause malnutrition and pancreatitis, and inflammation of the exocrine pancreas that promotes development of pancreatic ductal adenocarcinoma (PDAC), a deadly pancreatic neoplasm. The cellular and molecular mechanisms that maintain acinar cell function and whose dysregulation can lead to tissue damage and chronic pancreatitis are poorly understood. It was suggested that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis, but it is unknown whether impaired autophagy is a cause or a consequence of pancreatitis. To address this question, we generated Atg7(Δpan) mice that lack the essential autophagy-related protein 7 (ATG7) in pancreatic epithelial cells. Atg7(Δpan) mice exhibit severe acinar cell degeneration, leading to pancreatic inflammation and extensive fibrosis. Whereas ATG7 loss leads to the expected decrease in autophagic flux, it also results in endoplasmic reticulum (ER) stress, accumulation of dysfunctional mitochondria, oxidative stress, activation of AMPK, and a marked decrease in protein synthetic capacity that is accompanied by loss of rough ER. Atg7(Δpan) mice also exhibit spontaneous activation of regenerative mechanisms that initiate acinar-to-ductal metaplasia (ADM), a process that replaces damaged acinar cells with duct-like structures.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Moores Cancer Center, University of California, San Diego (UCSD) School of Medicine, La Jolla CA 92093-0636;
authors.forename: Laura
authors.initials: L
authors.lastname: Antonucci
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Moores Cancer Center, University of California, San Diego (UCSD) School of Medicine, La Jolla CA 92093-0636; Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, SE-413 45 Gothenburg, Sweden;
authors.forename: Johan B
authors.initials: JB
authors.lastname: Fagman
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Moores Cancer Center, University of California, San Diego (UCSD) School of Medicine, La Jolla CA 92093-0636;
authors.forename: Ju Youn
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Moores Cancer Center, University of California, San Diego (UCSD) School of Medicine, La Jolla CA 92093-0636; Department of Laboratory Medicine, Medical University of Vienna, Vienna, 1090, Austria;
authors.forename: Jelena
authors.initials: J
authors.lastname: Todoric
authors.affiliation: Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, CA 90073;
authors.forename: Ilya
authors.initials: I
authors.lastname: Gukovsky
authors.affiliation: National Center for Microscopy and Imaging Research, UCSD, La Jolla, CA 92093.
authors.forename: Mason
authors.initials: M
authors.lastname: Mackey
authors.affiliation: National Center for Microscopy and Imaging Research, UCSD, La Jolla, CA 92093.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Moores Cancer Center, University of California, San Diego (UCSD) School of Medicine, La Jolla CA 92093-0636; karinoffice@ucsd.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D061354:Acinar Cells / Q000502:physiology*; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006706:Homeostasis / Q000502:physiology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000172:deficiency*; D010179:Pancreas / Q000166:cytology*; D014176:Protein Biosynthesis / Q000502:physiology*
chemical_list: C502661:Atg7 protein, mouse; D008869:Microtubule-Associated Proteins; D000071193:Autophagy-Related Protein 7
keywords: ATG7; autophagy; pancreatitis; protein synthesis