Why Do Mutations in the Ubiquitously Expressed Housekeeping Gene<i>IMPDH1</i>Cause Retina-Specific Photoreceptor Degeneration?

Bowne, Sara J.; Liu, Qin; Sullivan, Lori S.; Zhu, Jiankun; Spellicy, Catherine J.; Rickman, Catherine Bowes; Pierce, Eric A.; Daiger, Stephen P.

doi:10.1167/iovs.06-0207

Cited by 57 publications

(69 citation statements)

References 23 publications

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“…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 hereafter designated IMPDH1(514) (20,21)). Both retinal isoforms IMPDH1(546) and IMPDH1(595) contain a 32-residue C-terminal extension.…”

Section: Imp Dehydrogenase (Impdh)mentioning

confidence: 99%

IMP Dehydrogenase Type 1 Associates with Polyribosomes Translating Rhodopsin mRNA

Mortimer

McGrew

et al. 2008

Journal of Biological Chemistry

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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...

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Section: Imp Dehydrogenase (Impdh)mentioning

confidence: 99%

IMP Dehydrogenase Type 1 Associates with Polyribosomes Translating Rhodopsin mRNA

Mortimer

McGrew

et al. 2008

Journal of Biological Chemistry

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“…The 1.3 kb HindIII fragment containing the hIRBP promoter was cloned into the pCI mammalian expression vector (Promega) between the CMV promoter and the chimeric intron sequence. Kpn I/Not I fragments containing the cDNA for the retinal isoforms were inserted into this plasmid [11]. The TGA stop-codon for IMPDH1 was then changed to GGA encoding Gly using QuikChange® (Stratagene).…”

Section: Plasmids Construction and Mutagenesismentioning

confidence: 99%

“…The pET-32Ek/LIC plasmids containing cDNA for retinal specific isoforms of IMPDH1 were used as templates to generate the corresponding D226N mutants using QuikChange [11]. These plasmids express the retinal isoforms as fusion proteins containing thioredoxin, His and RNase S peptide N-terminal tags.…”

Section: Protein Purificationmentioning

confidence: 99%

“…To the first approximation, IMPDH1 is constitutively expressed and IMPDH2 is amplified in proliferating tissues [9,10]. IMPDH1 predominates in the retina [11].…”

Section: Introductionmentioning

confidence: 99%

“…We have recently discovered that human retina contains two novel isoforms of IMPDH1, IMPDH1(546) (major) and IMPDH1(595) (minor) derived from alternative mRNA splicing [these proteins are also known as IMPDH1α/IMPDH1(13b) and IMPDHγ/IMPDH1(A+13b), respectively] [11,17]. Both IMPDH1(546) and IMPDH1(595) contain a 32 residue C-terminal extension while IMPDH1(595) has an additional 49 residues on the N-terminus.…”

Section: Introductionmentioning

confidence: 99%

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Retinal isoforms of inosine 5′-monophosphate dehydrogenase type 1 are poor nucleic acid binding proteins

Cobb

Spellicy

et al. 2008

Archives of Biochemistry and Biophysics

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The RP 10 form of autosomal dominant retinitis pigmentosa (adRP) is caused by mutations in the widely expressed protein inosine 5′-monophosphate dehydrogenase type 1 (IMPDH1). These mutations have no effect on the enzymatic activity of IMPDH1, but do perturb the association of IMPDH1 with nucleic acids. Two newly discovered retinal-specific isoforms, IMPDH1(546) and IMPDH1 (595) (595) is also similar to the canonical IMPDH1 and unaffected by the D226N mutation. However, unlike the canonical IMPDH1, the retinal specific isoforms do not bind significant fractions of a random pool of oligonucleotides. This observation indicates that the C-terminal extension unique to the retinal isoforms blocks the nucleic acid binding site of the IMPDH1, and thus uniquely regulates protein function within photoreceptors.

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The gateway to guanine nucleotides: Allosteric regulation of IMP dehydrogenases

et al. 2022

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Inosine 5′‐monophosphate dehydrogenase (IMPDH) is an evolutionarily conserved enzyme that mediates the first committed step in de novo guanine nucleotide biosynthetic pathway. It is an essential enzyme in purine nucleotide biosynthesis that modulates the metabolic flux at the branch point between adenine and guanine nucleotides. IMPDH plays key roles in cell homeostasis, proliferation, and the immune response, and is the cellular target of several drugs that are widely used for antiviral and immunosuppressive chemotherapy. IMPDH enzyme is tightly regulated at multiple levels, from transcriptional control to allosteric modulation, enzyme filamentation, and posttranslational modifications. Herein, we review recent developments in our understanding of the mechanisms of IMPDH regulation, including all layers of allosteric control that fine‐tune the enzyme activity.

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Why Do Mutations in the Ubiquitously Expressed Housekeeping GeneIMPDH1Cause Retina-Specific Photoreceptor Degeneration?

Cited by 57 publications

References 23 publications

IMP Dehydrogenase Type 1 Associates with Polyribosomes Translating Rhodopsin mRNA

IMP Dehydrogenase Type 1 Associates with Polyribosomes Translating Rhodopsin mRNA

Retinal isoforms of inosine 5′-monophosphate dehydrogenase type 1 are poor nucleic acid binding proteins

The gateway to guanine nucleotides: Allosteric regulation of IMP dehydrogenases

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