Transcription Repression of CRY2 via PER2 Interaction Promotes Adipogenesis.
Transcription Repression of CRY2 via PER2 Interaction Promotes Adipogenesis.
复制标题
通过 PER2 相互作用抑制 CRY2 的转录可促进脂肪生成。
DOI：
10.1080/10985549.2023.2253710
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发表时间：
2023
影响因子：
5.3
通讯作者：
Ma,Ke
中科院分区：
文献类型：
--
作者：
Li,Weini;Xiong,Xuekai;Kiperman,Tali;Ma,Ke
生物钟由转录-翻译反馈环驱动，隐花色素2（cryptochrome 2，CRP2）抑制CLOCK/BMAL1诱导的转录激活。尽管生物钟在脂肪形成调控中的作用已经确定，但是否在脂肪细胞生物学中起作用的是β 2阻遏物活性仍不清楚。在这里，我们确定了一个关键的半胱氨酸残基介导的相互作用与周期2（PER2）的THE2。我们进一步证明了这种机制是抑制生物钟控制的Wnt信号传导以促进脂肪形成所必需的。在白色脂肪库中富集了HSP2蛋白，并通过成脂分化强烈诱导。通过定点诱变，我们确定了与PER 2介导异二聚体复合物形成的环内432处的保守的PER 2半胱氨酸，该异二聚体复合物形成赋予转录抑制。C432突变破坏PER2的关联，而不影响BMAL1结合，导致时钟转录激活的抑制丧失。在前脂肪细胞中，而C432增强脂肪细胞分化，阻遏缺陷型C432突变体抑制了这一过程。此外，沉默的p53 2减弱，而稳定的p53 2的KL 001显着增加脂肪细胞的成熟。从机制上讲，我们表明，Wnt途径的转录抑制组件的脂肪形成的基础是BMP2调制。总的来说，我们的研究结果阐明了促进脂肪细胞发育的β 2介导的抑制机制，并暗示其作为肥胖时钟干预靶点的潜力。
The circadian clock is driven by a transcriptional-translational feedback loop, and cryptochrome 2 (CRY2) represses CLOCK/BMAL1-induced transcription activation. Despite the established role of clock in adipogenic regulation, whether the CRY2 repressor activity functions in adipocyte biology remains unclear. Here we identify a critical cysteine residue of CRY2 that mediates interaction with Period 2 (PER2). We further demonstrate that this mechanism is required for repressing circadian clock-controlled Wnt signaling to promote adipogenesis. CRY2 protein is enriched in white adipose depots and robustly induced by adipogenic differentiation. Via site-directed mutagenesis, we identified that a conserved CRY2 cysteine at 432 within the loop interfacing with PER2 mediates heterodimer complex formation that confers transcription repression. C432 mutation disrupted PER2 association without affecting BMAL1 binding, leading to loss of repression of clock transcription activation. In preadipocytes, whereas CRY2 enhanced adipocyte differentiation, the repression-defective C432 mutant suppressed this process. Furthermore, silencing of CRY2 attenuated, while stabilization of CRY2 by KL001 markedly augmented adipocyte maturation. Mechanistically, we show that transcriptional repression of Wnt pathway components underlies CRY2 modulation of adipogenesis. Collectively, our findings elucidate a CRY2-mediated repression mechanism that promotes adipocyte development, and implicate its potential as a clock intervention target for obesity.