Deletion of the WD40 domain of ATG16L1 exacerbates acute pancreatitis, abolishes LAP-like non-canonical autophagy and slows trypsin degradation

Chvanov, Michael, Voronina, Svetlana, Jefferson, Matthew, Mayer, Ulrike ORCID: https://orcid.org/0000-0003-2328-0052, Sutton, Robert, Criddle, David N., Wileman, Thomas and Tepikin, Alexei V. (2025) Deletion of the WD40 domain of ATG16L1 exacerbates acute pancreatitis, abolishes LAP-like non-canonical autophagy and slows trypsin degradation. Autophagy, 21 (1). pp. 210-222. ISSN 1554-8627

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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
Additional Information: Data availability statement: The data that support the findings of this study are available from the first/corresponding author (MC) upon reasonable request. Funding Information: The work was supported by the Medical Research Council [MR/T002220/1].
Uncontrolled Keywords: amylase,caerulein,cholecystokinin,endocytic vacuoles,lc3-associated phagocytosis,palmitoleic acid,molecular biology,cell biology ,/dk/atira/pure/subjectarea/asjc/1300/1312
Faculty \ School:
Faculty of Medicine and Health Sciences > Norwich Medical School
Faculty of Science > School of Biological Sciences
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Centres > Metabolic Health
Faculty of Medicine and Health Sciences > Research Groups > Gastroenterology and Gut Biology
Related URLs:
Depositing User: LivePure Connector
Date Deposited: 14 Jan 2025 00:59
Last Modified: 14 Jan 2025 00:59
URI: https://ueaeprints.uea.ac.uk/id/eprint/98192
DOI: 10.1080/15548627.2024.2392478

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