MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein
MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein
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DOI：
10.1042/bj20121126
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发表时间：
2013-07-15
影响因子：
4.1
通讯作者：
Ayer, Donald E.
中科院分区：
文献类型：
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作者：
Han, Kyoung-Sim;Ayer, Donald E.
MondoA-Mlx转录复合物通过响应于糖酵解中的第一反应中间体G6 P（葡萄糖6-磷酸）激活靶基因表达而在葡萄糖稳态中起关键作用。TXNIP（硫氧还蛋白相互作用蛋白）是MondoA的直接和葡萄糖响应性靶点，当G6 P水平增加时，通过限制葡萄糖摄取触发负反馈回路。在本研究中，我们发现TXNIP的表达也被AICAR（5-氨基-4-咪唑甲酰胺呋喃核糖苷）和腺苷激活。使用药理学抑制剂和嘌呤代谢酶的基因敲除，我们建立了AICAR和腺苷的TXNIP诱导需要它们的细胞摄取和代谢为腺嘌呤核苷酸。AICAR诱导TXNIP依赖于MondoA，但不依赖于AMPK（AMP活化蛋白激酶）活化和钙。本研究的结果有两个重要的意义。首先，除了激活AMPK之外，AICAR可能通过调节MondoA-Mlx活性在其流入腺嘌呤核苷酸库之后对基因表达具有AMPK非依赖性作用。其次，MondoA-Mlx复合物感测升高水平的G6 P和腺嘌呤核苷酸以触发糖酵解的TXNIP依赖性反馈抑制。我们建议，这种机制作为一个检查点，以恢复代谢稳态。
The MondoA-Mlx transcription complex plays a pivotal role in glucose homoeostasis by activating target gene expression in response to G6P (glucose 6-phosphate), the first reaction intermediate in glycolysis. TXNIP (thioredoxin-interacting protein) is a direct and glucose-responsive target of MondoA that triggers a negative-feedback loop by restricting glucose uptake when G6P levels increase. We show in the present study that TXNIP expression is also activated by AICAR (5-amino-4-imidazolecarboxamide ribofuranoside) and adenosine. Using pharmacological inhibitors and genetic knockdowns of purine metabolic enzymes, we establish that TXNIP induction by AICAR and adenosine requires their cellular uptake and metabolism to adenine nucleotides. AICAR induction of TXNIP depended on MondoA, but was independent of AMPK (AMP-activated protein kinase) activation and calcium. The findings of the present study have two important implications. First, in addition to activating AMPK, AICAR may have AMPK-independent effects on gene expression by regulating MondoA-Mlx activity following its flux into the adenine nucleotide pool. Secondly, MondoA-Mlx complexes sense elevated levels of G6P and adenine nucleotides to trigger a TXNIP-dependent feedback inhibition of glycolysis. We propose that this mechanism serves as a checkpoint to restore metabolic homoeostasis.