School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Rheumatology Division, Escola Paulista de Medicina, Universidade Federal de Sao Paulo, Sao Paulo, SP, 04023-062, Brazil.
School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
Dev Biol. 2021 Oct;478:89-101. doi: 10.1016/j.ydbio.2021.05.017. Epub 2021 May 25.
Inosine monophosphate dehydrogenase (IMPDH) catalyzes the rate-limiting step in de novo guanine nucleotide biosynthesis. Its activity is negatively regulated by the binding of GTP. IMPDH can form a membraneless subcellular structure termed the cytoophidium in response to certain changes in the metabolic status of the cell. The polymeric form of IMPDH, which is the subunit of the cytoophidium, has been shown to be more resistant to the inhibition by GTP at physiological concentrations, implying a functional correlation between cytoophidium formation and the upregulation of GTP biosynthesis. Herein we demonstrate that zebrafish IMPDH1b and IMPDH2 isoforms can assemble abundant cytoophidium in most of cultured cells under stimuli, while zebrafish IMPDH1a shows distinctive properties of forming the cytoophidium in different cell types. Point mutations that disrupt cytoophidium structure in mammalian models also prevent the aggregation of zebrafish IMPDHs. In addition, we discover the presence of the IMPDH cytoophidium in various tissues of larval and adult fish under normal growth conditions. Our results reveal that polymerization and cytoophidium assembly of IMPDH can be a regulatory machinery conserved among vertebrates, and with specific physiological purposes.
肌苷单磷酸脱氢酶（IMPDH）催化从头合成鸟嘌呤核苷酸的限速步骤。其活性受到 GTP 结合的负调控。IMPDH 可以响应细胞代谢状态的某些变化，形成无膜的细胞内亚结构，称为细胞浆。IMP DH 的聚合形式，即细胞浆的亚基，已被证明在生理浓度下对 GTP 的抑制更具抗性，这意味着细胞浆形成与 GTP 生物合成的上调之间存在功能相关性。本文证明，在刺激下，斑马鱼 IMPDH1b 和 IMPDH2 同工型可在大多数培养细胞中组装丰富的细胞浆，而斑马鱼 IMPDH1a 在不同细胞类型中显示出形成细胞浆的独特特性。破坏哺乳动物模型中细胞浆结构的点突变也阻止了斑马鱼 IMPDH 的聚集。此外，我们发现在正常生长条件下，幼虫和成年鱼的各种组织中都存在 IMPDH 细胞浆。我们的结果表明，IMP DH 的聚合和细胞浆组装可以是脊椎动物中保守的调节机制，并具有特定的生理目的。
