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

Calise, S. John; Purich, Daniel L.; Nguyen, Thi My Linh; Saleem, D.; Krueger, Claire; Yin, Joyce D.; Chan, Edward K. L.

doi:10.1242/jcs.183400

Cited by 36 publications

(35 citation statements)

References 44 publications

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“…IMPDH is the rate-limiting enzyme in guanine nucleotide biosynthesis and is dramatically upregulated by T cell activation (Dayton et al, 1994). IMPDH assembles into micron-scale structures in cultured cells, generally in response to pharmacological perturbations (Ji et al, 2006;Calise et al, 2014Calise et al, , 2016Carcamo et al, 2014;Keppeke et al, 2015;Zhao et al, 2015). The physiological relevance of these filamentous assemblies is unknown, although they are reported to be catalytically active (Chang et al, 2015;Zhao et al, 2015;Anthony et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

T cell activation triggers reversible inosine-5′-monophosphate dehydrogenase assembly

Duong‐Ly

Kuo

Johnson

et al. 2018

Journal of Cell Science

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T cell-mediated adaptive immunity requires naïve, unstimulated T cells to transition from a quiescent metabolic state into a highly proliferative state upon T cell receptor engagement. This complex process depends on transcriptional changes mediated by Ca-dependent NFAT signaling, mTOR-mediated signaling and increased activity of the guanine nucleotide biosynthetic inosine-5'-monophosphate (IMP) dehydrogenase 1 and 2 enzymes (IMPDH1 and IMPDH2, hereafter IMPDH). Inhibitors of these pathways serve as potent immunosuppressants. Unexpectedly, we discovered that all three pathways converge to promote the assembly of IMPDH protein into micron-scale macromolecular filamentous structures in response to T cell activation. Assembly is post-transcriptionally controlled by mTOR and the Ca influx regulator STIM1. Furthermore, IMPDH assembly and catalytic activity were negatively regulated by guanine nucleotide levels, suggesting a negative feedback loop that limits biosynthesis of guanine nucleotides. Filamentous IMPDH may be more resistant to this inhibition, facilitating accumulation of the higher GTP levels required for T cell proliferation.

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Section: Introductionmentioning

confidence: 99%

T cell activation triggers reversible inosine-5′-monophosphate dehydrogenase assembly

Duong‐Ly

Kuo

Johnson

et al. 2018

Journal of Cell Science

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“…IMPDH is the rate-limiting enzyme in guanine nucleotide biosynthesis and is dramatically upregulated by T cell activation (Dayton et al, 1994). IMPDH has been recently reported to assemble into micron-scale structures in cultured cells, generally in response to pharmacological perturbations Calise et al, 2016;Carcamo et al, 2014;Ji et al, 2006;Keppeke et al, 2015;Zhao et al, 2015). The physiological relevance of these filamentous assemblies is unknown, though they are reported to be catalytically active (Anthony et al, 2017;Chang et al, 2015;Zhao et al, 2015).…”

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confidence: 99%

T Cell Activation Triggers Reversible Inosine-5'-Monophosphate Dehydrogenase Assembly

Duong‐Ly¹,

Kuo

Johnson

et al. 2018

Preprint

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T cell-mediated adaptive immunity requires naïve, unstimulated T cells to transition from a quiescent metabolic state into a highly proliferative state upon T cell receptor engagement.This complex process depends on transcriptional changes mediated by Ca 2+ -dependent NFAT signaling, mTOR-mediated signaling and increased activity of the guanine nucleotide biosynthetic enzyme inosine-5'-monophosphate (IMP) dehydrogenase (IMPDH). Inhibitors of these pathways serve as potent immunosuppressants. Unexpectedly, we discovered that all three pathways converge to promote the assembly of IMPDH protein into micron-scale macromolecular filamentous structures in response to T cell activation. Assembly is posttranscriptionally controlled by mTOR and the Ca 2+ influx regulator STIM1. Furthermore, IMPDH assembly and catalytic activity were negatively regulated by guanine nucleotide levels, suggesting a negative feedback loop that limits biosynthesis of guanine nucleotides. Filamentous IMPDH may be more resistant to this inhibition, facilitating accumulation of the higher GTP levels required for T cell proliferation.

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“…Of special interest, some conditions that promote RR structures in cultured cells may mimic the tumor environment. Amino acid deprivation, such as glutamine and serine, and also excess glycine are some of the conditions that promote RR assembly and may point to plausible mechanisms for RR structure assembly in ALM tumor samples, which characteristically present unbalanced nutrient pools within the tumor microenvironment (Calise et al, , ).…”

Section: Discussionmentioning

confidence: 99%

IMP dehydrogenase rod/ring structures in acral melanomas

Keppeke

Barcelos

Fernandes

et al. 2020

Pigment Cell Melanoma Res

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Acral lentiginous melanoma (ALM) is a rare subtype of melanoma with aggressive behavior. IMPDH enzyme, involved in de novo GTP biosynthesis, has been reported to assemble into large filamentary structures called rods/rings (RR) or cytoophidium (cellular snakes). RR assembly induces a hyperactive state in IMPDH, usually to supply a high demand for GTP nucleotides, such as in highly proliferative cells. We investigate whether aggressive melanoma tumor cells present IMPDH‐based RR structures. Forty‐five ALM paraffin‐embedded tissue samples and 59 melanocytic nevi were probed with anti‐IMPDH2 antibody. Both the rod‐ and ring‐shaped RR could be observed, with higher frequency in ALM. ROC curve analyzing the proportions of RR‐positive cells in ALM versus nevi yielded a 0.88 AUC. Using the cutoff of 5.5% RR‐positive cells, there was a sensitivity of 80% and specificity of 85% for ALM diagnosis. In ALM, 36 (80%) showed RR frequency above the cutoff, being classified as RR‐positive, compared with only 9 (15%) of the nevi (p < .001). Histopathology showed that 71% of the RR‐positive specimens presented Breslow thickness > 4.0mm, compared with only 29% in the RR‐low/negative (p = .039). We propose that screening for RR structures in biopsy specimens may be a valuable tool helping differentiate ALM from nevi and accessing tumor malignancy.

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

Cited by 36 publications

References 44 publications

T cell activation triggers reversible inosine-5′-monophosphate dehydrogenase assembly

T cell activation triggers reversible inosine-5′-monophosphate dehydrogenase assembly

T Cell Activation Triggers Reversible Inosine-5'-Monophosphate Dehydrogenase Assembly

IMP dehydrogenase rod/ring structures in acral melanomas

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