PDF(Pubmed)
Abstract：
The cytoophidium is an evolutionarily conserved subcellular structure formed by filamentous polymers of metabolic enzymes. In vertebrates, inosine monophosphate dehydrogenase (IMPDH), which catalyses the rate-limiting step in guanosine triphosphate (GTP) biosynthesis, is one of the best-known cytoophidium-forming enzymes. Formation of the cytoophidium has been proposed to alleviate the inhibition of IMPDH, thereby facilitating GTP production to support the rapid proliferation of certain cell types such as lymphocytes, cancer cells and pluripotent stem cells (PSCs). However, past studies lacked appropriate models to elucidate the significance of IMPDH cytoophidium under normal physiological conditions. In this study, we demonstrate that the presence of IMPDH cytoophidium in mouse PSCs correlates with their metabolic status rather than pluripotency. By introducing IMPDH2 Y12C point mutation through genome editing, we established mouse embryonic stem cell (ESC) lines incapable of forming IMPDH polymers and the cytoophidium. Our data indicate an important role of IMPDH cytoophidium in sustaining a positive feedback loop that couples nucleotide biosynthesis with upstream metabolic pathways. Additionally, we find that IMPDH2 Y12C mutation leads to decreased cell proliferation and increased DNA damage in teratomas, as well as impaired embryo development following blastocoel injection. Further analysis shows that IMPDH cytoophidium assembly in mouse embryonic development begins after implantation and gradually increases throughout fetal development. These findings provide insights into the regulation of IMPDH polymerisation in embryogenesis and its significance in coordinating cell metabolism and development.
摘要：
胞质是由代谢酶的丝状聚合物形成的进化上保守的亚细胞结构。在脊椎动物中，肌苷一磷酸脱氢酶（IMPDH），催化三磷酸鸟苷（GTP）生物合成中的限速步骤，是最著名的胞质形成酶之一。已提出形成胞质以减轻IMPDH的抑制，从而促进GTP的产生，以支持某些细胞类型如淋巴细胞的快速增殖，癌细胞和多能干细胞（PSC）。然而,过去的研究缺乏适当的模型来阐明在正常生理条件下IMPDH胞嘧啶的意义.在这项研究中,我们证明，小鼠PSC中IMPDH胞质的存在与它们的代谢状态相关，而不是多能性。通过基因组编辑引入IMPDH2Y12C点突变，我们建立了小鼠胚胎干细胞（ESC）系，不能形成IMPDH聚合物和胞质。我们的数据表明IMPDH胞质在维持将核苷酸生物合成与上游代谢途径耦合的正反馈回路中的重要作用。此外,我们发现IMPDH2Y12C突变导致畸胎瘤细胞增殖减少和DNA损伤增加,以及胚层注射后胚胎发育受损。进一步的分析表明，小鼠胚胎发育中的IMPDH胞质组装在植入后开始，并在整个胎儿发育过程中逐渐增加。这些发现为胚胎发生中IMPDH聚合的调节及其在协调细胞代谢和发育中的意义提供了见解。
