Molecular Cell Biology and Immunobiology of Mammalian Rod/Ring Structures

Carcamo, Wendy C.; Calise, S. John; Mühlen, Carlos Alberto von; Satoh, Minoru; Chan, Edward K. L.

doi:10.1016/b978-0-12-800097-7.00002-6

Cited by 55 publications

(79 citation statements)

References 117 publications

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“…The existence of the nuclear Rod structures is mentioned in review by Carcamo et al (2014). The unexpected localization of IMPDH2 in the nucleus is in agreement with the results from immunoprecipitation experiments showing the ability of IMPDH protein to bind to RNA and DNA (McLean et al 2004).…”

Section: Discussionsupporting

confidence: 73%

“…IMPDH inclusions, for instance, have been named "Rods and Rings" (R&R) according to their apparent shape (Dellavance et al 2009;Seelig et al 2011). Distinct cytoplasmic rings (~2-5 µm in diameter), rods (~3-10 µm in length) and intermediate structures, such as "figure-eights", twisted rings, elongated rings, or needle-like structures, were initially observed in a routine immunofluorescence screening using human autoantibodies (Carcamo et al 2011;Keppeke et al 2012;Carcamo et al 2014). These cytoplasmic inclusions are enriched in IMPDH type II (IMPDH2), which is highly abundant in neoplastic and differentiating cells (Natsumeda et al 1990;Konno et al 1991).…”

Section: Introductionmentioning

confidence: 99%

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Ultrastructure of Cytoplasmic and Nuclear Inosine-5’-Monophosphate Dehydrogenase 2 “Rods and Rings” Inclusions

Jůda

Šmigová

Kováčik

et al. 2014

J Histochem Cytochem.

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Inosine-5′-monophosphate dehydrogenase catalyzes the critical step in the de novo synthesis of guanosine nucleotides: the oxidation of inosine monophosphate to xanthosine monophosphate. This reaction can be inhibited by specific inhibitors, such as ribavirin or mycophenolic acid, which are widely used in clinical treatment when required to inhibit the proliferation of viruses or cells. However, it was recently found that such an inhibition affects the cells, leading to a redistribution of IMPDH2 and the appearance of IMPDH2 inclusions in the cytoplasm. According to their shape, these inclusions have been termed "Rods and Rings" (R&R). In this work, we focused on the subcellular localization of IMPDH2 protein and the ultrastructure of R&R inclusions. Using microscopy and western blot analysis, we show the presence of nuclear IMPDH2 in human cells. We also show that the nuclear pool has an ability to form Rod structures after inhibition by ribavirin. Concerning the ultrastructure, we observed that R&R inclusions in cellulo correspond to the accumulation of fibrous material that is not surrounded by a biological membrane. The individual fibers are composed of regularly repeating subunits with a length of approximately 11 nm. Together, our findings describe the localization of IMPDH2 inside the nucleus of human cells as well as the ultrastructure of R&R inclusions.

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Section: Discussionsupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Ultrastructure of Cytoplasmic and Nuclear Inosine-5’-Monophosphate Dehydrogenase 2 “Rods and Rings” Inclusions

Jůda

Šmigová

Kováčik

et al. 2014

J Histochem Cytochem.

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“…The one-carbon metabolic pathway enzyme SHMT catalyzes the conversion of serine to glycine and tetrahydrofolate (THF) to N -CH 2 -THF acts as a carbon donor in the reaction catalyzed by thymidylate synthase (TYMS), which converts deoxyuridine monophosphate (dUMP) into deoxythymidine monophosphate (dTMP). We previously reported that we could induce RR formation in vitro using a 24-h treatment of 10 µM pemetrexed (Carcamo et al, 2014), a folate antimetabolite that nonspecifically inhibits the activity of TYMS and dihydrofolate reductase (DHFR), as well as glycinamide ribonucleotide formyltransferase and aminoimidazole carboxamide ribonucleotide formyltransferase. With the knowledge that serine and glycine levels appear to be crucial in the control of RR formation and that their conversion catalyzed by SHMT also plays an important role in one-carbon metabolism, we sought to determine whether the induction of RR upon pemetrexed treatment was due to its inhibitory activity on dTMP synthesis or purine synthesis.…”

Section: Inhibitors Targeting Dihydrofolate Reductase Induce Rr Formamentioning

confidence: 99%

“…In this respect, RR structures can be effectively induced in any mammalian cell line tested to date by IMPDH inhibitors (mycophenolic acid or ribavirin) or by glutaminase inhibitors or acivicin] Chen et al, 2011;Ji et al, 2006). The glutamine analog azaserine also promotes RR or cytoophidium assembly in both human and Drosophila cells (Chen et al, 2011), as do the anti-folate pemetrexed (Carcamo et al, 2014), nucleoside analog decoyinine (Gunter et al, 2008), and the uridine analog deazauridine in mammalian cells (Chang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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‘Rod and ring’ formation from IMP dehydrogenase is regulated through the one-carbon metabolic pathway

Calise

Purich

Nguyen

et al. 2016

Journal of Cell Science

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ABSTRACT'Rods and rings' (RRs) are conserved, non-membrane-bound intracellular polymeric structures composed, in part, of inosine monophosphate dehydrogenase (IMPDH), a key enzyme leading to GMP and GTP biosynthesis. RR formation is induced by IMPDH inhibitors as well as glutamine deprivation. They also form upon treatment of cells with glutamine synthetase inhibitors. We now report that depriving cells of serine and glycine promotes RR formation, and we have traced these effects to dihydrofolate reductase (DHFR) and serine hydroxymethyltransferase-2 (SHMT2), pivotal enzymes in one-carbon metabolism and nucleotide biosynthesis. RR assembly is likewise induced upon DHFR inhibition by methotrexate or aminopterin as well as siRNA-mediated knockdown of DHFR or SHMT2. Because RR assembly occurs when guanine nucleotide biosynthesis is inhibited, and because RRs rapidly disassemble after the addition of guanine nucleotide precursors, RR formation might be an adaptive homeostatic mechanism, allowing IMPDH to sense changes in the one-carbon folate pathway.

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Biochemical communication between filament‐forming enzymes

Bearne

2024

BioEssays

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A host of metabolic enzymes reversibly self‐assemble to form membrane‐less, intracellular filaments under normal physiological conditions and in response to stress. Often, these enzymes reside at metabolic control points, suggesting that filament formation affords an additional regulatory mechanism. Examples include cytidine‐5′‐triphosphate (CTP) synthase (CTPS), which catalyzes the rate‐limiting step for the de novo biosynthesis of CTP; inosine‐5′‐monophosphate dehydrogenase (IMPDH), which controls biosynthetic access to guanosine‐5′‐triphosphate (GTP); and ∆1‐pyrroline‐5‐carboxylate (P5C) synthase (P5CS) that catalyzes the formation of P5C, which links the Krebs cycle, urea cycle, and proline metabolism. Intriguingly, CTPS can exist in co‐assemblies with IMPDH or P5CS. Since GTP is an allosteric activator of CTPS, the association of CTPS and IMPDH filaments accords with the need to coordinate pyrimidine and purine biosynthesis. Herein, a hypothesis is presented furnishing a biochemical connection underlying co‐assembly of CTPS and P5CS filaments – potent inhibition of CTPS by glutamate γ‐semialdehyde, the open‐chain form of P5C.

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Molecular Cell Biology and Immunobiology of Mammalian Rod/Ring Structures

Cited by 55 publications

References 117 publications

Ultrastructure of Cytoplasmic and Nuclear Inosine-5’-Monophosphate Dehydrogenase 2 “Rods and Rings” Inclusions

Ultrastructure of Cytoplasmic and Nuclear Inosine-5’-Monophosphate Dehydrogenase 2 “Rods and Rings” Inclusions

‘Rod and ring’ formation from IMP dehydrogenase is regulated through the one-carbon metabolic pathway

Biochemical communication between filament‐forming enzymes

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