Handling Editor: John Heath
ABSTRACT
Since deregulation of intracellular Ca2+ can lead to intracellular trypsin activation, and stromal interaction molecule-1 (STIM1) protein is the main regulator of Ca2+ homeostasis in pancreatic acinar cells, we explored the Ca2+ signaling in 37 STIM1 variants found in three pancreatitis patient cohorts. Extensive functional analysis of one particular variant, p.E152K, identified in three patients, provided a plausible link between dysregulated Ca2+ signaling within pancreatic acinar cells and chronic pancreatitis susceptibility. Specifically, p.E152K, located within the STIM1 EF-hand and sterile α-motif domain, increased the release of Ca2+ from the endoplasmic reticulum in patient-derived fibroblasts and transfected HEK293T cells. This event was mediated by altered STIM1–sarco/endoplasmic reticulum calcium transport ATPase (SERCA) conformational change and enhanced SERCA pump activity leading to increased store-operated Ca2+ entry (SOCE). In pancreatic AR42J cells expressing the p.E152K variant, Ca2+ signaling perturbations correlated with defects in trypsin activation and secretion, and increased cytotoxicity after cholecystokinin stimulation.
This article has an associated First Person interview with the first author of the paper.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: M.B., T.C., O.M.; Methodology: M.B., N.L., P.B.S., M.I., O.M.; Validation: M.F., J.L., M.I., W.B., O.M.; Formal analysis: M.B.; Investigation: M.B., R.P., F.A., P.B., E.M., S.M., P.D., C.L.M., F.C., N.L., M.F., B.D., P.B.S., M.I., W.B., W.G., J.-M.C.; Resources: J.L., C.F., O.M.; Writing - original draft: M.B., O.M.; Writing - review & editing: M.B., J.L., P.B.S., W.B., J.-M.C., T.C., O.M.; Visualization: M.B.; Supervision: J.L., O.M.; Project administration: O.M.; Funding acquisition: C.F., O.M.
Funding
M.B. was supported by the Association de Transfusion Sanguine et de Biogénétique Gaetan Saleun, the Ministerio de Economía y Competitividad (Spanish Ministry of Economy and Competitivity), reference BFU2015-69874-R and the Castilla-La Mancha Government, reference II-2018_11. R.P. and O.M. were supported by the French association Vaincre La Mucoviscidose and the Association de Transfusion Sanguine et de Biogénétique Gaetan Saleun. F.A. was supported by a post-doctoral grant from Aviesan (ITMO IHP). M.F. was supported by the Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Foundation) grant # 310030-141113, the Association des Pancréatites Chroniques Héréditaires and the Institut National de la Santé et de la Recherche Médicale (INSERM), France. This work was supported by Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada (HSFC) and NSERC operating grants to M.I. and a Natural Sciences and Engineering Research Council of Canada (NSERC) operating grant to P.S.
Supplementary information
Supplementary information available online at https://jcs.biologists.org/lookup/doi/10.1242/jcs.244012.supplemental
- Received January 24, 2020.
- Accepted December 24, 2020.
- © 2021. Published by The Company of Biologists Ltd
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