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Mol. Biosci."],"abstract":"<jats:p>The type 2 Ca<jats:sup>2+<\/jats:sup>-dependent activator protein for secretion (CAPS2\/CADPS2) regulates dense-core vesicle trafficking and exocytosis and is involved in the regulated release of catecholamines, peptidergic hormones, and neuromodulators. CAPS2 is expressed in the pancreatic exocrine acinar cells that produce and secrete digestive enzymes. However, the functional role of CAPS2 in vesicular trafficking and\/or exocytosis of non-regulatory proteins in the exocrine pancreas remains to be determined. Here, we analyzed the morpho-pathological indicators of the pancreatic exocrine pathway in <jats:italic>Cadps2<\/jats:italic>-deficient mouse models using histochemistry, biochemistry, and electron microscopy. We used whole exosome sequencing to identify <jats:italic>CADPS2<\/jats:italic> variants in patients with chronic pancreatitis (CP). <jats:italic>Caps2\/Cadps2<\/jats:italic>-knockout (KO) mice exhibited morphophysiological abnormalities in the exocrine pancreas, including excessive accumulation of secretory granules (zymogen granules) and their amylase content in the cytoplasm, deterioration of the fine intracellular membrane structures (disorganized rough endoplasmic reticulum, dilated Golgi cisternae, and the appearance of empty vesicles and autophagic-like vacuoles), as well as exocrine pancreatic cell injury, including acinar cell atrophy, increased fibrosis, and inflammatory cell infiltration. Pancreas-specific <jats:italic>Cadps2<\/jats:italic> conditional KO mice exhibited pathological abnormalities in the exocrine pancreas similar to the global <jats:italic>Cadps2<\/jats:italic> KO mice, indicating that these phenotypes were caused either directly or indirectly by CAPS2 deficiency in the pancreas. Furthermore, we identified a rare variant in the exon3 coding region of <jats:italic>CADPS2<\/jats:italic> in a non-alcoholic patient with CP and showed that <jats:italic>Cadps2-dex3<\/jats:italic> mice lacking CAPS2 exon3 exhibited symptoms similar to those exhibited by the <jats:italic>Cadps2<\/jats:italic> KO and cKO mice. These results suggest that CAPS2 is critical for the proper functioning of the pancreatic exocrine pathway, and its deficiency is associated with a risk of pancreatic acinar cell pathology.<\/jats:p>","DOI":"10.3389\/fmolb.2022.1040237","type":"journal-article","created":{"date-parts":[[2022,11,7]],"date-time":"2022-11-07T06:54:50Z","timestamp":1667804090000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Loss of CAPS2\/Cadps2 leads to exocrine pancreatic cell injury and intracellular accumulation of secretory granules in mice"],"prefix":"10.3389","volume":"9","author":[{"given":"Yotaroh","family":"Sato","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miho","family":"Tsuyusaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromi","family":"Takahashi-Iwanaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rena","family":"Fujisawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Masamune","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shin","family":"Hamada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryotaro","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoichi","family":"Kakuta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumi","family":"Yamaguchi-Kabata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamio","family":"Furuse","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeharu","family":"Wakana","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takuya","family":"Shimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rika","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yo","family":"Shinoda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Goitsuka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"So","family":"Maezawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsushi","family":"Sadakata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshitake","family":"Sano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teiichi","family":"Furuichi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/s0167-4889(96)00146-2","article-title":"TGN38 and its orthologues: roles in post-TGN vesicle formation and maintenance of TGN morphology","volume":"1355","author":"Banting","year":"1997","journal-title":"Biochim. 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