Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.
Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.
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DOI：
10.1016/j.isci.2022.104125
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发表时间：
2022-04-15
期刊：
影响因子：
5.8
通讯作者：
Lawrence MC
中科院分区：
文献类型：
--
作者：
Darden CM;Vasu S;Mattke J;Liu Y;Rhodes CJ;Naziruddin B;Lawrence MC
胰岛通过产生激素和其他诱导适应性细胞和全身反应的因子来响应代谢和炎症应激。在此，我们发现高糖和精氨酸诱导的ER应激产生的细胞内Ca 2+（[Ca 2 +]i）和ROS信号激活钙调神经磷酸酶（CN）/NFATc 2和PI 3 K/AKT以维持β细胞的身份和功能。这部分归因于内分泌分化基因RFX 6的直接诱导和几种β细胞“不允许”基因（包括MCT 1）的抑制。CN/NFATc 2分别将p300和HDAC 1靶向RFX 6和MCT 1启动子以诱导和抑制基因转录。相比之下，长期暴露于应激、过度刺激[Ca 2 +]i或CN/NFATc 2的扰动会导致RFX 6的下调和MCT 1的诱导。这些发现揭示CN/NFATc 2和PI 3 K/AKT在急性应激期间维持β细胞功能，但是β细胞在Ca 2 +/CN/NFATc 2信号传导丧失或耗尽时去分化为功能障碍状态。它们进一步证明了靶向CN/NFATc 2恢复β细胞功能的效用。急性代谢和炎性应激激活β细胞中的Ca 2 +/CN/NFATc 2信号传导。NFATc 2诱导分化基因并抑制β细胞中不允许的基因。分子相互作用;内分泌学;糖尿病学;细胞生物学
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 Ca2+ ([Ca2+]i) 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 RFX6 and suppression of several β-cell “disallowed” genes, including MCT1. CN/NFATc2 targeted p300 and HDAC1 to RFX6 and MCT1 promoters to induce and suppress gene transcription, respectively. In contrast, prolonged exposure to stress, hyperstimulated [Ca2+]i, or perturbation of CN/NFATc2 resulted in downregulation of RFX6 and induction of MCT1. 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 Ca2+/CN/NFATc2 signaling. They further demonstrate the utility of targeting CN/NFATc2 to restore β-cell function Acute metabolic and inflammatory stress activates Ca2+/CN/NFATc2 signaling in β-cells NFATc2 induces differentiation genes and suppresses disallowed genes in β-cells Chronic stress hyperstimulates [Ca2+]i and delinks NFAT transcriptional activity Loss or exhaustion of Ca2+/CN/NFATc2 signaling results in β-cell dedifferentiation Molecular biology; Molecular interaction; Endocrinology; Diabetology; Cell biology
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影响因子：
7.7
作者：
Demozay D;Tsunekawa S;Briaud I;Shah R;Rhodes CJ
通讯作者：
Rhodes CJ
DOI：
10.1073/pnas.0912596106
发表时间：
2009-12-29
影响因子：
11.1
作者：
Lawrence, Michael C.;Shao, Chunli;Cobb, Melanie H.
通讯作者：
Cobb, Melanie H.
影响因子：
7.7
作者：
Lawrence, MC;Bhatt, HS;Easom, RA
通讯作者：
Easom, RA
影响因子：
16.6
作者：
Brereton, Melissa F.;Iberl, Michaela;Shimomura, Kenju;Zhang, Quan;Adriaenssens, Alice E.;Proks, Peter;Spiliotis, Ioannis I.;Dace, William;Mattis, Katia K.;Ramracheya, Reshma;Gribble, Fiona M.;Reimann, Frank;Clark, Anne;Rorsman, Patrik;Ashcroft, Frances M.
通讯作者：
Ashcroft, Frances M.
影响因子：
4.8
作者：
Lawrence, Michael C.;Naziruddin, Bashoo;Mcglynn, Kathleen
通讯作者：
Mcglynn, Kathleen