Darden Carly M, Vasu Srividya, Mattke Jordan, Liu Yang, Rhodes Christopher J, Naziruddin Bashoo, Lawrence Michael C
Islet Cell Laboratory, Baylor Scott & White Research Institute, Dallas, TX 75204, USA.
Institute of Biomedical Studies, Baylor University, Waco, TX 76706, USA.
iScience. 2022 Mar 19;25(4):104125. doi: 10.1016/j.isci.2022.104125. eCollection 2022 Apr 15.
Pancreatic islets respond to metabolic and inflammatory stress by producing hormones and other factors that induce adaptive cellular and systemic responses. Here we show that intracellular Ca ([Ca]) and ROS signals generated by high glucose and cytokine-induced ER stress activate calcineurin (CN)/NFATc2 and PI3K/AKT to maintain β-cell identity and function. This was attributed in part by direct induction of the endocrine differentiation gene and suppression of several β-cell "disallowed" genes, including . CN/NFATc2 targeted p300 and HDAC1 to and promoters to induce and suppress gene transcription, respectively. In contrast, prolonged exposure to stress, hyperstimulated [Ca], or perturbation of CN/NFATc2 resulted in downregulation of and induction of . These findings reveal that CN/NFATc2 and PI3K/AKT maintain β-cell function during acute stress, but β-cells dedifferentiate to a dysfunctional state upon loss or exhaustion of Ca/CN/NFATc2 signaling. They further demonstrate the utility of targeting CN/NFATc2 to restore β-cell function.
胰岛通过产生诱导适应性细胞和全身反应的激素及其他因子来应对代谢和炎症应激。在此我们表明，高糖和细胞因子诱导的内质网应激所产生的细胞内钙（[Ca]）和活性氧信号激活钙调神经磷酸酶（CN）/活化T细胞核因子c2（NFATc2）以及磷脂酰肌醇-3激酶（PI3K）/蛋白激酶B（AKT），以维持β细胞的特性和功能。这部分归因于内分泌分化基因的直接诱导以及包括……在内的几个β细胞“不允许”基因的抑制。CN/NFATc2分别靶向p300和组蛋白去乙酰化酶1（HDAC1）至……和……启动子，以诱导和抑制基因转录。相反，长时间暴露于应激、过度刺激的[Ca]或CN/NFATc2的扰动导致……的下调和……的诱导。这些发现揭示，CN/NFATc2和PI3K/AKT在急性应激期间维持β细胞功能，但β细胞在Ca/CN/NFATc2信号丧失或耗竭时会去分化为功能失调状态。它们进一步证明了靶向CN/NFATc2以恢复β细胞功能的效用。
