IMP Dehydrogenase Type 1 Associates with Polyribosomes Translating Rhodopsin mRNA

Abstract

IMP dehydrogenase (IMPDH) catalyzes the pivotal step in guanine nucleotide biosynthesis. Here we show that both IMPDH type 1 (IMPDH1) and IMPDH type 2 are associated with polyribosomes, suggesting that these housekeeping proteins have an unanticipated role in translation regulation. This interaction is mediated by the subdomain, a region of disputed function that is the site of mutations that cause retinal degeneration. The retinal isoforms of IMPDH1 also associate with polyribosomes. The most common disease-causing mutation, D226N, disrupts the polyribosome association of at least one retinal IMPDH1 isoform. Finally, we find that IMPDH1 is associated with polyribosomes containing rhodopsin mRNA. Because any perturbation of rhodopsin expression can trigger apoptosis in photoreceptor cells, these observations suggest a likely pathological mechanism for IMPDH1-mediated hereditary blindness. We propose that IMPDH coordinates the translation of a set of mRNAs, perhaps by modulating localization or degradation. IMP dehydrogenase (IMPDH)2 catalyzes the reaction that controls the entry of purines into the guanine nucleotide pool, and thus controls proliferation (1). The enzyme is a homotetramer; each monomer is composed of a catalytic (␤/␣) 8 barrel and a subdomain containing two CBS domains (named for the related domain in cystathionine ␤-synthase) (Fig. 1). Deletion of the subdomain has no effect on enzymatic activity (2, 3), and the function of the subdomain in IMPDH is currently under debate. CBS domains act as adenosine nucleotide-binding modules in several proteins (4 -9), and a similar role has been proposed for the CBS domains of IMPDH (5), but we and others have been unable to confirm this function in IMPDH (10 -13). Notably, the CBS domains of IMPDH share little sequence identity with the other proteins, so it would not be surprising if their function has diverged. The subdomain does appear to coordinately regulate the adenine and guanine nucleotide pool in Escherichia coli, although the molecular mechanism of this process has not yet been elucidated (11). We have discovered that IMPDH binds single-stranded nucleic acids and that the subdomain mediates this interaction (10, 15). IMPDH associates with RNA in tissue culture cells, which suggests that this housekeeping enzyme is involved in translation, splicing, or some other feature of RNA metabolism (10, 15). Others report that IMPDH binds DNA and may be involved in gene expression (16, 17). These observations suggest that IMPDH has a "moonlighting" function involving nucleic acid that is mediated by the subdomain.Mammals have two IMPDH genes, encoding IMPDH1 and IMPDH2, and most tissues express both isozymes (18,19). In contrast, only IMPDH1 appears to be expressed in the retina; in addition, retina contains distinct IMPDH1 isoforms generated by alternative mRNA splicing as follows: IMPDH1(546) (major) and IMPDH1(595) (minor) ( Fig. 1; these proteins are also known as IMPDH1␣/IMPDH1(13b) and IMPDH␥/IMPDH1(Aϩ13b), respectively; the canonical enzyme is hereaft...

A Regulatory Role of the Bateman Domain of IMP Dehydrogenase in Adenylate Nucleotide Biosynthesis

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Undercover: gene control by metabolites and metabolic enzymes

“…5B). IMPDH can bind RNA and polysomes and has been implicated in selective control of translation (Mortimer et al 2008). Studies in Drosophila showed that IMPDH is also a sequence-specific DNA-binding transcriptional repressor that binds unwound CT-rich regulatory DNA elements ( Fig.…”

Role of CBS and Bateman Domains in Phosphorylation-Dependent Regulation of a CLC Anion Channel

“…Bateman domains interact with diverse regulatory ligands, including adenosine nucleosides (18), cytoplasmic ions (22), charged membrane domains (23), DNA and RNA (24,25), and other proteins (26). Interactions with regulatory ligands induce Bateman domain conformational changes that control protein function (19,21).…”