Université de Brest, INSERM, EFS, UMR 1078, GGB, F-29200 Brest, France
Centro Regional de Investigaciones Biomédicas (CRIB) and Facultad de Medicina de Albacete, Universidad de Castilla-La Mancha, 02002 Albacete, Spain.
J Cell Sci. 2021 Feb 10;134(3):jcs244012. doi: 10.1242/jcs.244012.
Since deregulation of intracellular Ca can lead to intracellular trypsin activation, and stromal interaction molecule-1 (STIM1) protein is the main regulator of Ca homeostasis in pancreatic acinar cells, we explored the Ca 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 Ca 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 Ca 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 Ca entry (SOCE). In pancreatic AR42J cells expressing the p.E152K variant, Ca 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.
由于细胞内 Ca 浓度的调节失控会导致细胞内胰蛋白酶的激活，而基质相互作用分子-1（STIM1）蛋白是胰腺腺泡细胞中 Ca 离子稳态的主要调节剂，因此我们研究了在三个胰腺炎患者队列中发现的 37 种 STIM1 变体的 Ca 信号转导。对在三个患者中发现的一个特定变体 p.E152K 进行了广泛的功能分析，为胰腺腺泡细胞内 Ca 信号调节失控与慢性胰腺炎易感性之间提供了一个合理的联系。具体来说，位于 STIM1 EF 手和无菌 α 基序域内的 p.E152K 增加了源自患者来源成纤维细胞和转染的 HEK293T 细胞的内质网中 Ca 的释放。该事件是通过改变 STIM1-肌浆/内质网钙转运 ATP 酶（SERCA）构象变化和增强 SERCA 泵活性导致的储存操纵的 Ca 内流（SOCE）介导的。在表达 p.E152K 变体的 AR42J 胰腺细胞中，Ca 信号转导的改变与胰蛋白酶激活和分泌缺陷相关，并且在胆囊收缩素刺激后细胞毒性增加。本文有该论文第一作者的相关第一人称采访。
