Abstract
ABSTRACTCytidine triphosphate synthase (CTPS) and inosine monophosphate dehydrogenase (IMPDH) (both of which have two isoforms) can form fiber-like subcellular structures termed ‘cytoophidia’ under certain circumstances in mammalian cells. Although it has been shown that filamentation of CTPS downregulates its activity by disturbing conformational changes, the activity of IMPDH within cytoophidia is still unclear. Most previous IMPDH cytoophidium studies were performed under conditions involving inhibitors that impair GTP synthesis. Here, we show that IMPDH forms cytoophidia without inhibition of GTP synthesis. First, we find that an elevated intracellular CTP concentration or treatment with 3′-deazauridine, a CTPS inhibitor, promotes IMPDH cytoophidium formation and increases the intracellular GTP pool size. Moreover, restriction of cell growth triggers the disassembly of IMPDH cytoophidia, implying that their presence is correlated with active cell metabolism. Finally, we show that the presence of IMPDH cytoophidia in mouse pancreatic islet cells might correlate with nutrient uptake in the animal. Collectively, our findings reveal that formation of IMPDH cytoophidia reflects upregulation of purine nucleotide synthesis, suggesting that the IMPDH cytoophidium plays a role distinct from that of the CTPS cytoophidium in controlling intracellular nucleotide homeostasis.
Highlights
Nucleotides are essential for DNA and RNA synthesis, but are involved in various metabolic processes and signaling transductions
We show that regulation of the Inosine monophosphate dehydrogenase (IMPDH) cytoophidium is different from that of the cytidine triphosphate synthase (CTPS) cytoophidium
CTPS and IMPDH form two types of cytoophidia CTPS and IMPDH have been identified as the main components of cytoophidia in mammalian cells (Carcamo et al, 2011; Chen et al, 2011)
Summary
Nucleotides are essential for DNA and RNA synthesis, but are involved in various metabolic processes and signaling transductions. Received 3 June 2015; Accepted 13 August 2015 structure termed ‘rods and rings’ or the ‘cytoophidium’ (Carcamo et al, 2011; Ingerson-Mahar et al, 2010; Ji et al, 2006; Liu, 2010; Noree et al, 2014, 2010) This structure is not membrane-bound and is not associated with any known organelle in mammalian cells (Thomas et al, 2012). Different types of cytoophidia displayed similar filamentous morphology, but the proportions of them changed with various inductions; the IMPDH inhibitors mycophenolic acid (MPA) and Ribavirin induce only IMPDH-based cytoophidia, whereas 6-diazo-5-oxo-Lnorleucine (DON), which interrupts purine and pyrimidine biosynthesis, triggers filamentation of both enzymes (Keppeke et al, 2015) These results suggest that formation of CTPS and IMPDH cytoophidia can be regulated independently
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
