Txnip balances metabolic and growth signaling via PTEN disulfide reduction
Txnip balances metabolic and growth signaling via PTEN disulfide reduction
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DOI：
10.1073/pnas.0800293105
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发表时间：
2008-03-11
影响因子：
11.1
通讯作者：
Davis, Roger A.
中科院分区：
文献类型：
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作者：
Hui, Simon T. Y.;Andres, Allen M.;Davis, Roger A.
硫氧还蛋白相互作用蛋白(TXNIP)抑制硫氧还蛋白NADPH依赖的蛋白质二硫键还原。完全TXNIP基因敲除(TKO)小鼠通过将骨骼肌和心脏的燃料依赖从脂肪和酮体转移到葡萄糖来不适当地适应长时间的禁食。TKO小鼠在氧化组织(骨骼肌和心脏)中表现出Akt信号、胰岛素敏感性和糖酵解增加，但在脂肪组织(肝脏和脂肪组织)中则没有。骨骼肌和心脏中Akt的选择性激活与线粒体燃料氧化受损和氧化(失活)PTEN的积累有关，PTEN的活性依赖于两个关键半胱氨酸残基的还原。肌肉和心脏特异的TXNIP基因敲除小鼠重现了TKO小鼠的代谢表型，肝脏特异的TXNIP基因敲除小鼠与WT小鼠相似。来自基因敲除小鼠的胚胎成纤维细胞也积累了氧化的(非活性的)PTEN，并升高了Akt的磷酸化。此外，由于线粒体燃料氧化受损，它们的生长速度更快，对厌氧糖酵解的依赖性增加，并且它们对阿霉素促进的呼吸依赖性细胞凋亡具有抵抗力。在没有TXNIP的情况下，PTEN的氧化失活和Akt的激活减弱了线粒体的呼吸，导致了PTEN硫氧还蛋白NADPH还原激活的竞争性抑制剂NADH的积累。这些发现表明，在非生脂组织中，TXNIP需要维持足够的硫氧还蛋白NADPH活性，以还原地重新激活氧化的PTEN，并对抗Akt下游信号。
Thioredoxin-interacting protein (Txnip) inhibits thioredoxin NADPH-dependent reduction of protein disulfides. Total Txnip knockout (TKO) mice adapted inappropriately to prolonged fasting by shifting fuel dependence of skeletal muscle and heart from fat and ketone bodies to glucose. TKO mice exhibited increased Akt signaling, insulin sensitivity, and glycolysis in oxidative tissues (skeletal muscle and hearts) but not in lipogenic tissues (liver and adipose tissue). The selective activation of Akt in skeletal muscle and hearts was associated with impaired mitochondrial fuel oxidation and the accumulation of oxidized (inactive) PTEN, whose activity depends on reduction of two critical cysteine residues. Whereas muscle- and heart-specific Txnip knockout mice recapitulated the metabolic phenotype exhibited by TKO mice, liver-specific Txnip knockout mice were similar to WT mice. Embryonic fibroblasts derived from knockout mice also accumulated oxidized (inactive) PTEN and had elevated Akt phosphorylation. In addition, they had faster growth rates and increased dependence on anaerobic glycolysis due to impaired mitochondrial fuel oxidation, and they were resistant to doxorubicin-facilitated respiration-dependent apoptosis. In the absence of Txnip, oxidative inactivation of PTEN and subsequent activation of Akt attenuated mitochondrial respiration, resulting in the accumulation of NADH, a competitive inhibitor of thioredoxin NADPH-reductive activation of PTEN. These findings indicate that, in nonlipogenic tissues, Txnip is required to maintain sufficient thioredoxin NADPH activity to reductively reactivate oxidized PTEN and oppose Akt downstream signaling.