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, 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:	http://www.scopus.com/inward/record.url?...
Depositing User:	LivePure Connector
Date Deposited:	14 Jan 2025 00:59
Last Modified:	06 Feb 2025 12:31
URI:	https://ueaeprints.uea.ac.uk/id/eprint/98192
DOI:	10.1080/15548627.2024.2392478

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