Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis
| Autor: | 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 |
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| Rok vydání: | 2020 |
| Předmět: |
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 |
| Zdroj: | 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 |
| ISSN: | 2352-345X |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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