Loss of CAPS2/Cadps2 Leads to Exocrine Pancreatic Cell Injury and Intracellular Accumulation of Secretory Granules in Mice

Sato Y, Tsuyusaki M, Takahashi-Iwanaga H, Fujisawa R, Masamune A, Hamada S, Matsumoto R, Tanaka Y, Kakuta Y, Yamaguchi-Kabata Y, Furuse T, Wakana S, Shimura T, Kobayashi R, Shinoda Y, Goitsuka R, Maezawa S, Sadakata T, Sano Y, and Furuichi T., Frontiers in Molecular Biosciences, 9:1040237, 2022.

https://doi.org/10.3389/fmolb.2022.1040237

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Exocrine function of pancreatic acinar cells is essential for the secretion of digestive enzymes and imperative for food metabolism. Dysfunction of pancreatic exocrine regulation deteriorates the quality of life and decreases life expectancy. Chronic pancreatitis is one of the predominant cause of pancreatic dysfunction. Risk factors include alcohol, smoking and certain genetic alterations. However, the underlying genetic mechanisms are not fully understood. Our research team (Tokyo University of Science, Hokkaido University, Tohoku University, RIKEN BioResource Research Center, Tokyo University of Pharmacy and Life Science, Gunma University) revealed that CAPS2/Cadps2*, a known regulator for neuromodulator secretion, is also critical for efficient pancreatic secretion of amylase, an enzyme essential in breaking down carbohydrates and CAPS2/Cadps2 deficiency causes injury of acinar cells responsible for exocrine pancreas.

The Ca2+-dependent activator protein for secretion 2 (CAPS2/Cadps2) plays a pivotal role in regulating trafficking and exocytosis of dense-core vesicles for the release of neurotransmitters, neuropeptides, and peptide hormones. It is a contradictory issue that Cadps2-knockout (KO) mice exhibit slightly increased food consumption, but they have smaller body size and lower body weight throughout life compared to wild-type (WT) mice. Importantly, CAPS2 is expressed in the exocrine pancreas, an important organ to secrete digestive enzymes by exocytosis of dense-core vesicles or secretory granules (SGs)/zymogen granules. However, whether CAPS2 affects the vesicular trafficking and/or exocytosis pathway of SGs containing digestive enzymes in pancreatic acinar cells remains to be determined. The research team utilized three genetically modified mice (Cadps2 KO mice, pancreatic-specific Cadps2 cKO mice, and subcellular localization-deficient Cadps2-dex3 mice) to challenge this question.

CAPS2 deficiency causes various abnormalities, such as deterioration in the fine structure of the rough ER (rER) and Golgi network for SG synthesis and trafficking, excessive intracellular accumulation of SGs and their content amylase, and the appearance of aberrant vesicular structures, thereby decreasing amylase activity in the serum. In addition, KO mice exhibited pathophysiological phenotypes including a progressive loss of acini and increase of adipocytes and interstitial cells, leading to pancreatic acinar cell atrophy, fibrosis, and intense focal inflammation, which was reminiscent of that observed in experimentally-induced pancreatitis mouse models. Pancreas-specific Cadps2-cKO mice also exhibited abnormal cytoplasmic accumulation of SGs and amylase, similar to global Cadps2-KO mice.