Keppeke Gerson Dierley, Chang Chia Chun, Peng Min, Chen Li-Yu, Lin Wei-Cheng, Pai Li-Mei, Andrade Luis Eduardo Coelho, Sung Li-Ying, Liu Ji-Long
1Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, OX1 3PT UK.
2Institute of Biotechnology, National Taiwan University, Taipei, 106 Taiwan, ROC.
Cell Div. 2018 Jun 15;13:5. doi: 10.1186/s13008-018-0038-0. eCollection 2018.
Inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in de novo GTP biosynthesis, plays an important role in cell metabolism and proliferation. It has been demonstrated that IMPDH can aggregate into a macrostructure, termed the cytoophidium, in mammalian cells under a variety of conditions. However, the regulation and function of the cytoophidium are still elusive.
In this study, we report that spontaneous filamentation of IMPDH is correlated with rapid cell proliferation. Intracellular IMP accumulation promoted cytoophidium assembly, whereas elevated GTP level triggered disassociation of aggregates. By using IMPDH2 CBS domain mutant cell models, which are unable to form the cytoophidium, we have determined that the cytoophidium is of the utmost importance for maintaining the GTP pool and normal cell proliferation in the condition that higher IMPDH activity is required.
Together, our results suggest a novel mechanism whereby cytoophidium assembly upregulates IMPDH activity and mediates guanine nucleotide homeostasis.
肌苷单磷酸脱氢酶（IMPDH）是从头合成GTP的限速酶，在细胞代谢和增殖中起重要作用。已经证明，在多种条件下，IMPDH在哺乳动物细胞中可聚集成一种称为细胞蛇的宏观结构。然而，细胞蛇的调节和功能仍然不清楚。
在本研究中，我们报道IMPDH的自发丝状化与细胞快速增殖相关。细胞内IMP积累促进细胞蛇组装，而GTP水平升高触发聚集体解离。通过使用无法形成细胞蛇的IMPDH2 CBS结构域突变细胞模型，我们确定在需要更高IMPDH活性的情况下，细胞蛇对于维持GTP池和正常细胞增殖至关重要。
总之，我们的结果提示了一种新机制，即细胞蛇组装上调IMPDH活性并介导鸟嘌呤核苷酸稳态。
