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Mareninova OA, Dillon DL, Wightman CJM, et al. Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis. Cell Mol Gastroenterol Hepatol. 2021;13(2):599-622doi: 10.1016/j.jcmgh.2021.09.017.
Mareninova, O. A., Dillon, D. L., Wightman, C. J. M., Yakubov, I., Takahashi, T., Gaisano, H. Y., Munson, K., Ohmuraya, M., Dawson, D., Gukovsky, I., & Gukovskaya, A. S. (2021). Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis. Cellular and molecular gastroenterology and hepatology, 13(2), 599-622. https://doi.org/10.1016/j.jcmgh.2021.09.017
Mareninova, Olga A, et al. "Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis." Cellular and molecular gastroenterology and hepatology vol. 13,2 (2021): 599-622. doi: https://doi.org/10.1016/j.jcmgh.2021.09.017
Mareninova OA, Dillon DL, Wightman CJM, Yakubov I, Takahashi T, Gaisano HY, Munson K, Ohmuraya M, Dawson D, Gukovsky I, Gukovskaya AS. Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis. Cell Mol Gastroenterol Hepatol. 2021 Oct 02;13(2):599-622. doi: 10.1016/j.jcmgh.2021.09.017. Epub 2021 Oct 02. PMID: 34610499; PMCID: PMC8715155.
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Cell Mol Gastroenterol Hepatol. 2021 Oct 02;13(2):599-622. doi: 10.1016/j.jcmgh.2021.09.017. Epub 2021 Oct 02.

Rab9 Mediates Pancreatic Autophagy Switch From Canonical to Noncanonical, Aggravating Experimental Pancreatitis.

Cellular and molecular gastroenterology and hepatology

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

Affiliations

  1. Department of Medicine, Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, California.
  2. Department of Medicine, Los Angeles, California.
  3. Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
  4. Department of Physiology, Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, California.
  5. Department of Genetics, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
  6. Department of Pathology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.
  7. Department of Medicine, Los Angeles, California; VA Greater Los Angeles Healthcare System, Los Angeles, California. Electronic address: [email protected].

PMID: 34610499 PMCID: PMC8715155 DOI: 10.1016/j.jcmgh.2021.09.017

Abstract

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 (Rab9

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 Rab9

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.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: Alternative Autophagy; Autophagosome; Rab GTPase; RabGDI

References

  1. Nat Cell Biol. 2014 Jun;16(6):495-501 - PubMed
  2. Am J Physiol Gastrointest Liver Physiol. 2012 Nov 1;303(9):G993-G1003 - PubMed
  3. Nature. 2009 Oct 1;461(7264):654-8 - PubMed
  4. J Cell Biol. 2002 Feb 4;156(3):511-8 - PubMed
  5. Autophagy. 2020 Nov;16(11):2084-2097 - PubMed
  6. Biochem J. 2008 Oct 1;415(1):67-75 - PubMed
  7. Gastroenterology. 2019 Jan;156(1):254-272.e11 - PubMed
  8. FEBS J. 2021 Jan;288(1):36-55 - PubMed
  9. Dev Cell. 2018 Apr 9;45(1):114-131.e8 - PubMed
  10. Curr Opin Cell Biol. 2020 Apr;63:1-10 - PubMed
  11. Autophagy. 2021 Jan;17(1):1-382 - PubMed
  12. Autophagy. 2014 Jul;10(7):1154-66 - PubMed
  13. Commun Integr Biol. 2016 Jul 22;9(4):e1204498 - PubMed
  14. Pancreas. 2019 Apr;48(4):459-470 - PubMed
  15. Proc Natl Acad Sci U S A. 2015 Nov 10;112(45):E6166-74 - PubMed
  16. Mol Cell. 2014 Jan 23;53(2):167-78 - PubMed
  17. Gastroenterology. 2007 Mar;132(3):1127-51 - PubMed
  18. J Clin Invest. 2009 Nov;119(11):3340-55 - PubMed
  19. Am J Pathol. 2017 Dec;187(12):2726-2743 - PubMed
  20. Gastroenterology. 2018 Feb;154(3):689-703 - PubMed
  21. J Cell Biol. 2008 Jun 30;181(7):1065-72 - PubMed
  22. J Biol Chem. 2017 Apr 7;292(14):5957-5969 - PubMed
  23. J Lipid Res. 2006 Mar;47(3):467-75 - PubMed
  24. Adv Med Sci. 2019 Sep;64(2):315-323 - PubMed
  25. Gastroenterology. 2015 Mar;148(3):626-638.e17 - PubMed
  26. Autophagy. 2012 Jun;8(6):883-92 - PubMed
  27. J Clin Invest. 2015 Jan;125(1):33-41 - PubMed
  28. J Clin Invest. 2019 Feb 1;129(2):802-819 - PubMed
  29. Small GTPases. 2011 Jul;2(4):192-201 - PubMed
  30. J Cell Physiol. 2018 Sep;233(9):7080-7091 - PubMed
  31. Cell Mol Gastroenterol Hepatol. 2015 Nov 1;1(6):678-694 - PubMed
  32. Curr Opin Gastroenterol. 2016 Sep;32(5):429-435 - PubMed
  33. Annu Rev Cell Dev Biol. 2019 Oct 6;35:453-475 - PubMed
  34. Trends Cell Biol. 2005 Jul;15(7):356-63 - PubMed
  35. J Biol Chem. 2006 Feb 10;281(6):3370-81 - PubMed
  36. J Cell Biol. 2019 Jun 3;218(6):1908-1927 - PubMed
  37. Nat Rev Mol Cell Biol. 2009 Aug;10(8):513-25 - PubMed
  38. EMBO J. 2019 Aug 15;38(16):e99266 - PubMed
  39. Mol Biol Cell. 2017 Mar 15;28(6):712-715 - PubMed
  40. Gastroenterology. 2013 Jun;144(6):1180-93 - PubMed
  41. Autophagy. 2009 Jul;5(5):585-9 - PubMed
  42. Nat Rev Mol Cell Biol. 2011 Dec 14;13(1):7-12 - PubMed
  43. J Cell Biol. 2019 Mar 4;218(3):757-770 - PubMed
  44. Mol Cell. 2019 Oct 17;76(2):268-285 - PubMed
  45. FEBS Lett. 2010 Jun 18;584(12):2635-45 - PubMed
  46. Am J Pathol. 2009 Jan;174(1):14-20 - PubMed
  47. Sci Rep. 2017 Jun 6;7(1):2817 - PubMed

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