RASEF/Rab45 regulates the formation and sorting of zymogen granules and secretion of digestive enzymes by pancreatic acinar cells

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2024-10, Vol.1870 (7), p.167310, Article 167310
• Main Authors: Sato, Keiko, Kadowaki, Tomoko, Takenaka, Mamoru, Konishi, Mayo, Ando, Miyabi, Onodera, Takae, Tsukuba, Takayuki
• Format: Article
• Language: English
• Subjects: Acinar Cells - metabolism; Animals; Endoplasmic Reticulum - metabolism; Exocytosis; Lysosomes - metabolism; Male; Mice; Mice, Knockout; Organelle formation; Pancreas; Pancreas - metabolism; Pancreas, Exocrine - metabolism; Pancreatitis - chemically induced; Pancreatitis - metabolism; Pancreatitis - pathology; Protein Transport; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; Rab45; RASEF; Secretory Vesicles - metabolism; Trypsinogen - metabolism; Zymogen granules
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167310

The pancreas is a glandular organ with both endocrine and exocrine functions. Researchers have investigated the roles of several Rab proteins, which are major regulators of membrane trafficking, in pancreatic exocytosis of zymogen granules in exocrine cells, also known as acinar cells. However, detailed molecular mechanisms mediated by Rab proteins are not fully understood. RASEF/Rab45 is an atypical Rab GTPase that contains N-terminal EF-hand and coiled-coil domains, as well as a C-terminal Rab-GTPase domain. In this study, we investigated the in vivo role of RASEF in pancreatic acinar cells using RASEF-knockout (KO) mice. Morphological analyses revealed that pancreatic acinar cells in RASEF-KO mice had an increased number of zymogen granules and abnormal formations of organelles, such as the endoplasmic reticulum (ER) and lysosomes. Biochemical analyses showed that ER proteins were decreased, but digestive enzymes were increased in the RASEF-KO pancreas. Moreover, trypsinogen was activated and co-localized with the endo-lysosomal marker LAMP1 in RASEF-KO pancreas. Upon cerulein administration to induce acute pancreatitis, impaired enzyme release from the pancreas was observed in the serum of RASEF-KO mice. These findings suggest that RASEF likely regulates the formation and sorting of zymogen granules and secretion of digestive enzymes by pancreatic acinar cells. [Display omitted] •RASEF/Rab45 is highly expressed in pancreatic acinar cells.•RASEF-KO pancreatic acinar cells show an increased number of zymogen granules.•RASEF deficiency induces autophagy and abnormal formation of organelles.•Intracellular activation of trypsinogen occurs in RASEF-deficient pancreas.•RASEF deficiency impairs pancreatic enzyme release.