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Glycogen synthase kinase 3 drives thymocyte egress by suppressing β-catenin activation of Akt.

ABSTRACT: Molecular pathways controlling emigration of mature thymocytes from thymus to the periphery remain incompletely understood. Here, we show that T cell–specific ablation of glycogen synthase kinase 3 (GSK3) led to severely impaired thymic egress. In the absence of GSK3, β-catenin accumulated in the cytoplasm, where it associated with and activated Akt, leading to phosphorylation and degradation of Foxo1 and downregulation of Klf2 and S1P₁ expression, thereby preventing emigration of thymocytes. A cytoplasmic membrane-localized β-catenin excluded from the nucleus promoted Akt activation, suggesting a new function of β-catenin independent of its role as a transcriptional activator. Furthermore, genetic ablation of β-catenin, retroviral expression of a dominant negative Akt mutant, and transgenic expression of a constitutively active Foxo1 restored emigration of GSK3-deficient thymocytes. Our findings establish an essential role for GSK3 in thymocyte egress and reveal a previously unidentified signaling function of β-catenin in the cytoplasm.

SUBMITTER: Liu C

PROVIDER: S-EPMC8500522 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Glycogen synthase kinase 3 drives thymocyte egress by suppressing β-catenin activation of Akt.

Liu Chenfeng C Ma Lei L Wang Yuxuan Y Zhao Jiayi J Chen Pengda P Chen Xian X Wang Yingxin Y Hu Yanyan Y Liu Yun Y Jia Xian X Yang Zhanghua Z Yin Xingzhi X Wu Jianfeng J Wu Suqin S Zheng Haiping H Ma Xiaohong X Sun Xiufeng X He Ying Y Lin Lianghua L Fu Yubing Y Liao Kunyu K Zhou Xiaojuan X Jiang Shan S Fu Guofeng G Tang Jian J Han Wei W Chen Xiao Lei XL Fan Wenzhu W Hong Yazhen Y Han Jiahuai J Huang Xiangyang X Li Bo-An BA Xiao Nengming N Xiao Changchun C Fu Guo G Liu Wen-Hsien WH

Science advances 20211008 41

Molecular pathways controlling emigration of mature thymocytes from thymus to the periphery remain incompletely understood. Here, we show that T cell–specific ablation of glycogen synthase kinase 3 (GSK3) led to severely impaired thymic egress. In the absence of GSK3, β-catenin accumulated in the cytoplasm, where it associated with and activated Akt, leading to phosphorylation and degradation of Foxo1 and downregulation of Klf2 and S1P<sub>1</sub> expression, thereby preventing emigration of thy ...[more]

PMID: 34623920

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Project description:Background The neonatal heart maintains its entire regeneration capacity within days after birth. Using quantitative phosphoproteomics technology, we identified that SGK3 (serine/threonine-protein kinase 3) in the neonatal heart is highly expressed and activated after myocardial infarction. This study aimed to uncover the function and related mechanisms of SGK3 on cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. Methods and Results The effect of SGK3 on proliferation and oxygen glucose deprivation/reoxygenation- induced apoptosis in isolated cardiomyocytes was evaluated using cardiomyocyte-specific SGK3 overexpression or knockdown adenovirus5 vector. In vivo, gain- and loss-of-function experiments using cardiomyocyte-specific adeno-associated virus 9 were performed to determine the effect of SGK3 in cardiomyocyte proliferation and cardiac repair after apical resection or ischemia/reperfusion injury. In vitro, overexpression of SGK3 enhanced, whereas knockdown of SGK3 decreased, the cardiomyocyte proliferation ratio. In vivo, inhibiting the expression of SGK3 shortened the time window of cardiac regeneration after apical resection in neonatal mice, and overexpression of SGK3 significantly promoted myocardial repair and cardiac function recovery after ischemia/reperfusion injury in adult mice. Mechanistically, SGK3 promoted cardiomyocyte regeneration and myocardial repair after cardiac injury by inhibiting GSK-3β (glycogen synthase kinase-3β) activity and upregulating β-catenin expression. SGK3 also upregulated the expression of cell cycle promoting genes G1/S-specific cyclin-D1, c-myc (cellular-myelocytomatosis viral oncogene), and cdc20 (cell division cycle 20), but downregulated the expression of cell cycle negative regulators cyclin kinase inhibitor P 21 and cyclin kinase inhibitor P 27. Conclusions Our study reveals a key role of SGK3 on cardiac repair after apical resection or ischemia/reperfusion injury, which may reopen a novel therapeutic option for myocardial infarction.

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Glycogen synthase kinase 3 drives thymocyte egress by suppressing β-catenin activation of Akt.

Publications

Glycogen synthase kinase 3 drives thymocyte egress by suppressing β-catenin activation of Akt.

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