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Review
. 2015 Dec;26(12):746-757.
doi: 10.1016/j.tem.2015.09.012. Epub 2015 Oct 28.

Metabolic Enzymes Enjoying New Partnerships as RNA-Binding Proteins

Alfredo Castello  1 , Matthias W Hentze  2 , Thomas Preiss  3
Affiliations
Review

Metabolic Enzymes Enjoying New Partnerships as RNA-Binding Proteins

Alfredo Castello et al. Trends Endocrinol Metab. 2015 Dec.

Abstract

In the past century, few areas of biology advanced as much as our understanding of the pathways of intermediary metabolism. Initially considered unimportant in terms of gene regulation, crucial cellular fate changes, cell differentiation, or malignant transformation are now known to involve 'metabolic remodeling' with profound changes in the expression of many metabolic enzyme genes. This review focuses on the recent identification of RNA-binding activity of numerous metabolic enzymes. We discuss possible roles of this unexpected second activity in feedback gene regulation ('moonlighting') and/or in the control of enzymatic function. We also consider how metabolism-driven post-translational modifications could regulate enzyme-RNA interactions. Thus, RNA emerges as a new partner of metabolic enzymes with far-reaching possible consequences to be unraveled in the future.

Keywords: RNA; RNA-binding proteins; metabolic enzymes; metabolon; post-transcriptional regulation; post-translational modifications.

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Figures

Figure 1
Figure 1
Schematic Representation of RNA Interactome Capture. Living cell monolayers are irradiated with UV light to covalently link direct protein–RNA interactions. Polyadenylated RNA and covalently bound protein partners are isolated by oligo(dT) pull-down under denaturing conditions. After RNase treatment, the RNA-binding protein (RBP) repertoire is determined by quantitative mass spectrometry, comparing proteins isolated from crosslinked cells (cCL) with those present in a mock pull-down (noCL). Only proteins with consistent enrichment across replicates (encircled in red) are considered as the RNA interactome.
Figure 2
Figure 2
Iron Regulatory Protein 1 (IRP1) Functions as Cytosolic Aconitase and RNA-Binding Protein (RBP). (A) IRP1 binds to several mRNAs when not assembled with the 4Fe–4S cluster due to low intracellular concentrations of iron. Among the best-studied examples is the binding of IRP1 to the iron-responsive element (IRE) in the 5′ untranslated region (UTR) of the ferritin mRNA to repress its translation. Since this mRNA encodes an iron-storage protein, diminished ferritin levels will promote an increase of free iron. Conversely, IRP1 increases the stability of transferrin receptor mRNA when binding to IREs in its 3′ UTR. An increase in transferrin receptor levels will promote cellular iron uptake. (B) Conversely, when IRP1 bears a 4Fe–4S cluster due to high intracellular iron concentration, it becomes active as cytosolic aconitase, catalyzing the interconversion between citrate and isocitrate. (C) Ribbon diagram of IRP1 bound to an IRE (PDB 3SNP). (D) Ribbon diagram of IRP1 crystalized as aconitase with the active site 4Fe–4S cluster (shown in red) (PDB 2B3Y).
Figure 3
Figure 3
Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) moonlights as an RNA-Binding Protein (RBP) in Lymphocytes. (A) GAPDH binds the AU-rich element (ARE) present in the 3′ untranslated region (UTR) of interferon γ (IFNγ) mRNA in resting T cells relying on oxidative phosphorylation (OXPHOS), repressing IFNγ expression. (B) Engaged in glycolysis in activated T cells, GAPDH catalyzes the interconversion between glyceraldehyde-3-phosphate to d-glycerate-1,3-bisphosphate using NAD+ as cofactor . (C, D) Ribbon diagram of GAPDH bound to NAD either as a (C) monomer or (D) tetramer (PDB 1ZNQ).
Figure 4
Figure 4
Key Figure: Is RNA Regulated by or the Regulator of Metabolic Enzymes? Several distinct modes of RNA–enzyme interaction can be envisaged (A) RNA binding overlaps with the active site and/or cofactor-binding pocket (top left) or is distant to it (top right). RNA-binding activity could be regulated by metabolite-derived post-translational modifications (bottom left). RNA could further regulate enzyme localization, for example, by attachment to a cellular structure such as a membrane (bottom right). (B) RNA may also serve as scaffold for assembly of oligomers, or (C) multienzyme complexes into metabolons. See main text for further discussion.
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