Chvanov, Michael, Voronina, Svetlana, Jefferson, Matthew, Mayer, Ulrike, Sutton, Robert 
ORCID: 0000-0001-6600-562X, Criddle, David N ORCID: 0000-0003-2952-8450, Wileman, Thomas and Tepikin, Alexei V
(2024)
Deletion of the WD40 domain of ATG16L1 exacerbates acute pancreatitis, abolishes LAP-like non-canonical autophagy and slows trypsin degradation
Autophagy, 21 (1).
pp. 1-13.
ISSN 1554-8627, 1554-8635
Abstract
The WD40 domain (WDD) of ATG16L1 plays a pivotal role in non-canonical autophagy. This study examined the role of recently identified LAP-like non-canonical autophagy (LNCA) in acute pancreatitis. LNCA involves rapid single-membrane LC3 conjugation to endocytic vacuoles in pancreatic acinar cells. The rationale for this study was the previously observed presence of trypsin in the organelles undergoing LNCA; aberrant trypsin formation is an important factor in pancreatitis development. Here we report that the deletion of WDD (attained in ATG16L1[E230] mice) eliminated LNCA, aggravated caerulein-induced acute pancreatitis and suppressed the fast trypsin degradation observed in both a rapid caerulein-induced disease model and in caerulein-treated isolated pancreatic acinar cells. These experiments indicate that LNCA is a WDD-dependent mechanism and suggest that it plays not an activating but a protective role in acute pancreatitis. Furthermore, palmitoleic acid, another inducer of experimental acute pancreatitis, strongly inhibited LNCA, suggesting a novel mechanism of pancreatic lipotoxicity. Abbreviation: AMY: amylase; AP: acute pancreatitis; CASM: conjugation of Atg8 to single membranes; CCK: cholecystokinin; FAEE model: fatty acid and ethanol model; IL6: interleukin 6; LA: linoleic acid; LAP: LC3-associated phagocytosis; LMPO: lung myeloperoxidase; LNCA: LAP-like non-canonical autophagy; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MPO: myeloperoxidase; PMPO: pancreatic myeloperoxidase; POA: palmitoleic acid; WDD: WD40 domain; WT: wild type.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Amylase, caerulein, cholecystokinin, endocytic vacuoles, LC3-associated phagocytosis, palmitoleic acid |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 02 Sep 2024 15:38 |
| Last Modified: | 28 Feb 2026 20:40 |
| DOI: | 10.1080/15548627.2024.2392478 |
| Open Access URL: | https://doi.org/10.1080/15548627.2024.2392478 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3184200 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
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