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

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.