法国内克尔儿童研究所Ganna Panasyuk研究组的研究表明，3型磷脂酰肌醇-3激酶（PI3K）共激活生物钟促进嘌呤从头合成。该项研究成果发表在2023年7月6日出版的《自然—细胞生物学》杂志上。 研究人员发现3型PI3K在基因转录中具有被忽视的核功能，其可作为异二聚体转录因子和昼夜节律驱动Bmal1-Clock的共激活因子；PI3K以在自噬内吞作用和溶酶体降解中发挥脂质激酶的重要作用而闻名。在分子运输过程中，3型PI3K的典型前分解代谢功能依赖于脂质激酶Vps34和调节亚基Vps15组成的复合物。研究证明，尽管3型PI3K的两个亚基与RNA聚合酶II相互作用并与活性转录位点共定位，但细胞中Vps15的缺失会减弱Bmal1-Clock的转录活性。因此，研究人员证明核Vps34和Vps15之间存在非冗余关系，这反映在Vps34缺失细胞中细胞核Vps15的持续增加以及Vps15独立于其Vps34复合物共激活Bmal1-Clock的能力。

在生理学上，研究发现Vps15是肝脏代谢节律所必需的，并且出乎意料的是，它促进嘌呤核苷酸的从头合成。研究表明Vps15激活Ppat的转录，Ppat是催化产生肌苷单磷酸的关键酶，肌苷是嘌呤合成的关键中间体。最后，研究证明在抑制时钟转录活性的禁食过程中，Bmal1靶点Nr1d1和Ppat启动子上Vps15的水平降低。该研究结果为确定细胞核3型PI3K信号传导的复杂性以调节能量稳态时间调节开辟了途径。

据悉，代谢需要有节奏地波动，并依赖于生物钟与营养感知信号通路之间的协调，但仍未完全了解它们相互作用的机制。

附：英文原文

Title: Class 3 PI3K coactivates the circadian clock to promote rhythmic de novo purine synthesis

Author: Alkhoury, Chantal, Henneman, Nathaniel F., Petrenko, Volodymyr, Shibayama, Yui, Segaloni, Arianna, Gadault, Alexis, Nemazanyy, Ivan, Le Guillou, Edouard, Wolide, Amare Desalegn, Antoniadou, Konstantina, Tong, Xin, Tamaru, Teruya, Ozawa, Takeaki, Girard, Muriel, Hnia, Karim, Lutter, Dominik, Dibner, Charna, Panasyuk, Ganna

Issue&Volume: 2023-07-06

Abstract: Metabolic demands fluctuate rhythmically and rely on coordination between the circadian clock and nutrient-sensing signalling pathways, yet mechanisms of their interaction remain not fully understood. Surprisingly, we find that class 3 phosphatidylinositol-3-kinase (PI3K), known best for its essential role as a lipid kinase in endocytosis and lysosomal degradation by autophagy, has an overlooked nuclear function in gene transcription as a coactivator of the heterodimeric transcription factor and circadian driver Bmal1–Clock. Canonical pro-catabolic functions of class 3 PI3K in trafficking rely on the indispensable complex between the lipid kinase Vps34 and regulatory subunit Vps15. We demonstrate that although both subunits of class 3 PI3K interact with RNA polymerase II and co-localize with active transcription sites, exclusive loss of Vps15 in cells blunts the transcriptional activity of Bmal1–Clock. Thus, we establish non-redundancy between nuclear Vps34 and Vps15, reflected by the persistent nuclear pool of Vps15 in Vps34-depleted cells and the ability of Vps15 to coactivate Bmal1–Clock independently of its complex with Vps34. In physiology we find that Vps15 is required for metabolic rhythmicity in liver and, unexpectedly, it promotes pro-anabolic de novo purine nucleotide synthesis. We show that Vps15 activates the transcription of Ppat, a key enzyme for the production of inosine monophosphate, a central metabolic intermediate for purine synthesis. Finally, we demonstrate that in fasting, which represses clock transcriptional activity, Vps15 levels are decreased on the promoters of Bmal1 targets, Nr1d1 and Ppat. Our findings open avenues for establishing the complexity for nuclear class 3 PI3K signalling for temporal regulation of energy homeostasis.

DOI: 10.1038/s41556-023-01171-3

Source: https://www.nature.com/articles/s41556-023-01171-3

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