Abstract
BackgroundInosine 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.ResultsIn 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.ConclusionsTogether, our results suggest a novel mechanism whereby cytoophidium assembly upregulates IMPDH activity and mediates guanine nucleotide homeostasis.
Highlights
Inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in de novo GTP biosynthe‐ sis, plays an important role in cell metabolism and proliferation
To further explore the correlation between cytoophidium formation, purine metabolism and cell proliferation, we attempted to analyse the cytoophidium in a cell model with a high amount of IMPDH cytoophidia under normal culture conditions
We firstly labelled IMPDH in mouse induced pluripotent stem cells (iPSCs) and observed IMPDH cytoophidia in 82 ± 5.9% of the cells under normal culture condition (Fig. 1a, c). This shows that IMPDH cytoophidium assembly is a natural phenomenon in iPSCs
Summary
Inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in de novo GTP biosynthe‐ sis, plays an important role in cell metabolism and proliferation. The regulation and function of the cytoophidium are still elusive. Purine nucleotides are essential molecules for a variety of cell functions. They serve as the building blocks of DNA and RNA, and participate in cell metabolism as cofactors or energy donors, and are involved in cell signal transduction and cytoskeleton organisation. The precise regulation of nucleotide biosynthesis is crucial for regular cell metabolism [1]. Purine nucleotides can be synthesized by a salvage pathway or a de novo synthetic pathway. By the former purine free bases will be recycled by hypoxanthine/
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