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Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.

ABSTRACT: 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.

SUBMITTER: Darden CM

PROVIDER: S-EPMC8983383 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.

Darden Carly M CM Vasu Srividya S Mattke Jordan J Liu Yang Y Rhodes Christopher J CJ Naziruddin Bashoo B Lawrence Michael C MC

iScience 20220319 4

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 ...[more]

PMID: 35402865

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Dataset Information

Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.

Publications

Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.

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