Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental PancreatitisSummary
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 ho...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-01-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X21002071 |
| _version_ | 1798021339027603456 |
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| author | Olga A. Mareninova Dustin L. Dillon Carli J.M. Wightman Iskandar Yakubov Toshimasa Takahashi Herbert Y. Gaisano Keith Munson Masaki Ohmuraya David Dawson Ilya Gukovsky Anna S. Gukovskaya |
| author_facet | Olga A. Mareninova Dustin L. Dillon Carli J.M. Wightman Iskandar Yakubov Toshimasa Takahashi Herbert Y. Gaisano Keith Munson Masaki Ohmuraya David Dawson Ilya Gukovsky Anna S. Gukovskaya |
| author_sort | Olga A. Mareninova |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T17:12:30Z |
| format | Article |
| id | doaj.art-11feff5cad444a05b90bf2cb94aaf905 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-04-11T17:12:30Z |
| publishDate | 2022-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-11feff5cad444a05b90bf2cb94aaf9052022-12-22T04:12:51ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2022-01-01132599622Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental PancreatitisSummaryOlga A. Mareninova0Dustin L. Dillon1Carli J.M. Wightman2Iskandar Yakubov3Toshimasa Takahashi4Herbert Y. Gaisano5Keith Munson6Masaki Ohmuraya7David Dawson8Ilya Gukovsky9Anna S. Gukovskaya10Department of Medicine, Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, CaliforniaDepartment of Medicine, Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, CaliforniaDepartment of Medicine, Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, CaliforniaDepartment of Medicine, Los Angeles, CaliforniaDepartment of Medicine, University of Toronto, Toronto, Ontario, CanadaDepartment of Medicine, University of Toronto, Toronto, Ontario, CanadaDepartment of Physiology, Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, CaliforniaDepartment of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo, JapanDepartment of Pathology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CaliforniaDepartment of Medicine, Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, CaliforniaDepartment of Medicine, Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, California; Correspondence Address correspondence to: Anna Gukovskaya, PhD, AGAF, Pancreatic Research Group, UCLA/West Los Angeles VA Healthcare Center, 11301 Wilshire Boulevard, Building 258, Room 340, Los Angeles, California 90073. fax: (310) 268-4578.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.http://www.sciencedirect.com/science/article/pii/S2352345X21002071AutophagosomeAlternative AutophagyRab GTPaseRabGDI |
| spellingShingle | Olga A. Mareninova Dustin L. Dillon Carli J.M. Wightman Iskandar Yakubov Toshimasa Takahashi Herbert Y. Gaisano Keith Munson Masaki Ohmuraya David Dawson Ilya Gukovsky Anna S. Gukovskaya Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental PancreatitisSummary Cellular and Molecular Gastroenterology and Hepatology Autophagosome Alternative Autophagy Rab GTPase RabGDI |
| title | Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental PancreatitisSummary |
| title_full | Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental PancreatitisSummary |
| title_fullStr | Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental PancreatitisSummary |
| title_full_unstemmed | Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental PancreatitisSummary |
| title_short | Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental PancreatitisSummary |
| title_sort | rab9 mediates pancreatic autophagy switch from canonical to noncanonical aggravating experimental pancreatitissummary |
| topic | Autophagosome Alternative Autophagy Rab GTPase RabGDI |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X21002071 |
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