Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis
| العنوان: | Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis |
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| المؤلفون: | Keith Munson, Toshimasa Takahashi, Anna S. Gukovskaya, Iskandar Yakubov, Carli J. Wightman, Ilya Gukovsky, Olga A. Mareninova, Dustin L. Dillon, David W. Dawson, Herbert Y. Gaisano, Masaki Ohmuraya |
| المصدر: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 2, Pp 599-622 (2022) Cellular and molecular gastroenterology and hepatology, vol 13, iss 2 |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Autophagosome, IB, immunoblot, RC799-869, Vacuole, Acinar Cells, Mitochondrion, RabGDI, Arg-AP, L-arginine–induced acute pancreatitis, Cat, cathepsin, Oral and gastrointestinal, Mice, GTPase, guanosine triphosphatase, LC3, microtubule-associated protein 1 light chain 3, 2.1 Biological and endogenous factors, Aetiology, ANOVA, analysis of variance, Original Research, Chemistry, Gastroenterology, Diseases of the digestive system. Gastroenterology, Cell biology, medicine.anatomical_structure, Pancreas, 1.1 Normal biological development and functioning, ATG8, ATG5, SEM, standard error of the mean, ER, endoplasmic reticulum, ATG, autophagy-related (proteins), Underpinning research, Alternative Autophagy, medicine, Autophagy, AP, acute pancreatitis, Animals, CER, cerulein (ortholog of CCK), IF, immunofluorescence, RabGDI, Rab guanosine dissociation inhibitor, Rab9TG, transgenic mice overexpressing Rab9, Hepatology, Autophagosomes, medicine.disease, WT, wild-type, CCK, cholecystokinin-8, Pancreatitis, rab GTP-Binding Proteins, Digestive Diseases, Rab GTPase |
| الوصف: | Background Autophagosome, the central organelle in autophagy process, can assemble via canonical pathway mediated by LC3-II, the lipidated form of autophagy-related protein LC3/ATG8, or noncanonical pathway mediated by the small GTPase Rab9. Canonical autophagy is essential for exocrine pancreas homeostasis, and its disordering initiates and drives pancreatitis. The involvement of noncanonical autophagy has not been explored. We examine the role of Rab9 in pancreatic autophagy and pancreatitis severity. Methods We measured the effect of Rab9 on parameters of autophagy and pancreatitis responses using transgenic mice overexpressing Rab9 (Rab9TG) and adenoviral transduction of acinar cells. Effect of canonical autophagy on Rab9 was assessed in ATG5-deficient acinar cells. Results Pancreatic levels of Rab9 and its membrane-bound (active) form decreased in rodent pancreatitis models and in human disease. Rab9 overexpression stimulated noncanonical and inhibited canonical/LC3-mediated autophagosome formation in acinar cells through up-regulation of ATG4B, the cysteine protease that delipidates LC3-II. Conversely, ATG5 deficiency caused Rab9 increase in acinar cells. Inhibition of canonical autophagy in Rab9TG pancreas was associated with accumulation of Rab9-positive vacuoles containing markers of mitochondria, protein aggregates, and trans-Golgi. The shift to the noncanonical pathway caused pancreatitis-like damage in acinar cells and aggravated experimental pancreatitis. Conclusions The results show that Rab9 regulates pancreatic autophagy and indicate a mutually antagonistic relationship between the canonical/LC3-mediated and noncanonical/Rab9-mediated autophagy pathways in pancreatitis. Noncanonical autophagy fails to substitute for its canonical counterpart in protecting against pancreatitis. Thus, Rab9 decrease in experimental and human pancreatitis is a protective response to sustain canonical autophagy and alleviate disease severity. Graphical abstract |
| وصف الملف: | application/pdf |
| تدمد: | 2352-345X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::55cf84e7660abe7bc4aa24bb6ab842cfTest https://pubmed.ncbi.nlm.nih.gov/34610499Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....55cf84e7660abe7bc4aa24bb6ab842cf |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 2352345X |
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