BACKGROUND _ AIMS: Pancreatic acinar cells have an expanded apical endosomal system, the physiological and pathophysiological significance of which is still emerging. @entity12498 ( @entity12498 ) is an essential phospholipid generated by PIKfyve, which phosphorylates @entity8736 ( @entity25571 ). @entity12498 is necessary for maturation of early endosomes (EE) to late endosomes (LE). Inhibition of EE to LE trafficking enhances anterograde endosomal trafficking and secretion at the plasma membrane by default through a recycling endosome (RE) intermediate. We assessed the effects of modulating PIKfyve activity on apical trafficking and @entity788 responses in pancreatic acinar cells. METHODS: Inhibition of EE to LE trafficking was achieved using pharmacological inhibitors of PIKfyve, expression of dominant negative PIKfyve @entity68873 , or constitutively active @entity4814 -GTP @entity68874 . Anterograde endosomal trafficking was manipulated by expression of constitutively active and dominant negative @entity21220 mutants. The effects of these agents on secretion, endolysosomal exocytosis of lysosome associated membrane protein ( @entity3220 ), and trypsinogen activation in response to high-dose @entity13216 -8, @entity3645 and cigarette toxin was determined. RESULTS: PIKfyve inhibition increased basal and stimulated secretion. Adenoviral overexpression of PIKfyve decreased secretion leading to cellular death. Expression of @entity4814 -GTP @entity68874 or @entity21220 -GTP @entity25704 enhanced secretion. Conversely, dominant-negative @entity21220 -GDP @entity68875 reduced secretion. High-dose @entity13216 inhibited endolysosomal exocytosis that was reversed by PIKfyve inhibition. PIKfyve inhibition blocked intracellular trypsin accumulation and cellular damage responses to high @entity13216 -8, @entity286 toxin, and @entity3645 in both rodent and @entity1 acini. CONCLUSIONS: These data demonstrate that EE-LE trafficking acutely controls acinar secretion and the intracellular activation of zymogens leading to the pathogenicity of acute @entity788 .

Early to Late Endosome Trafficking Controls Secretion and Zymogen Activation in Rodent and XXXX Pancreatic Acinar Cells.

@entity1 :: ('9606', 'Species') :: ['human'] @entity286 :: ('4097', 'Species') :: ['tobacco'] @entity788 :: ('MESH:D010190', 'Disease') :: ['pancreatitis'] @entity25571 :: ('CHEBI:26034', 'Chemical') :: ['PI(3)P'] @entity3220 :: ('3916', 'Gene') :: ['LAMP1'] @entity21220 :: ('8766', 'Gene') :: ['Rab11a'] @entity68875 :: ('p|SUB|S|25|N', 'ProteinMutation') :: ['S25N'] @entity8736 :: ('MESH:C055525', 'Chemical') :: ['phosphatidylinositol-3-phosphate'] @entity68873 :: ('p|SUB|K|1877|E', 'ProteinMutation') :: ['K1877E'] @entity4814 :: ('5868', 'Gene') :: ['Rab5'] @entity68874 :: ('p|SUB|Q|79|L', 'ProteinMutation') :: ['Q79L'] @entity12498 :: ('MESH:C106336', 'Chemical') :: ['PI(3,5)P2', 'Phosphatidylinositol-3,5-bisphosphate'] @entity3645 :: ('MESH:D001647', 'Chemical') :: ['bile salts', 'bile acids'] @entity13216 :: ('885', 'Gene') :: ['CCK'] @entity25704 :: ('p|SUB|Q|70|L', 'ProteinMutation') :: ['Q70L']
@entity1 :: (9606,Species) :: ['Human']
