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Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions.

ABSTRACT: We report the in vivo regulation of Inosine-5´-monophosphate dehydrogenase 1 (IMPDH1) in the retina. IMPDH1 catalyzes the rate-limiting step in the de novo synthesis of guanine nucleotides, impacting the cellular pools of GMP, GDP and GTP. Guanine nucleotide homeostasis is central to photoreceptor cells, where cGMP is the signal transducing molecule in the light response. Mutations in IMPDH1 lead to inherited blindness. We unveil a light-dependent phosphorylation of retinal IMPDH1 at Thr159/Ser160 in the Bateman domain that desensitizes the enzyme to allosteric inhibition by GDP/GTP. When exposed to bright light, living mice increase the rate of GTP and ATP synthesis in their retinas; concomitant with IMPDH1 aggregate formation at the outer segment layer. Inhibiting IMPDH activity in living mice delays rod mass recovery. We unveil a novel mechanism of regulation of IMPDH1 in vivo, important for understanding GTP homeostasis in the retina and the pathogenesis of adRP10 IMPDH1 mutations.

SUBMITTER: Plana-Bonamaiso A

PROVIDER: S-EPMC7176436 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions.

Plana-Bonamaisó Anna A López-Begines Santiago S Fernández-Justel David D Junza Alexandra A Soler-Tapia Ariadna A Andilla Jordi J Loza-Alvarez Pablo P Rosa Jose Luis JL Miralles Esther E Casals Isidre I Yanes Oscar O de la Villa Pedro P Buey Ruben M RM Méndez Ana A

eLife 20200407

We report the in vivo regulation of Inosine-5´-monophosphate dehydrogenase 1 (IMPDH1) in the retina. IMPDH1 catalyzes the rate-limiting step in the de novo synthesis of guanine nucleotides, impacting the cellular pools of GMP, GDP and GTP. Guanine nucleotide homeostasis is central to photoreceptor cells, where cGMP is the signal transducing molecule in the light response. Mutations in IMPDH1 lead to inherited blindness. We unveil a light-dependent phosphorylation of retinal IMPDH1 at Thr<sup>159 ...[more]

PMID: 32254022

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Project description:BackgroundLotus (Nelumbo Adans.) is used as an herbal medicine and the flowers are a source of natural flavonoids. 'Da Sajin', which was firstly found in the plateau area, is a natural mutant in flower color with red streamers dyeing around white petals.ResultsThe LC-MS-MS results showed that eight anthocyanin compounds, including cyanidin 3-O-glucoside, cyanidin 3-O-galactoside, malvidin 3-O-galactoside, and malvidin 3-O-glucoside, were differentially enriched in red-pigmented tissues of the petals, whereas most of these metabolites were undetected in white tissues of the petals. Transcriptome profiling indicated that the relative high expression levels of structural genes, such as NnPAL, NnF3H, and NnANS, was inconsistent with the low anthocyanin concentration in white tissues. Members of the NnMYB and NnbHLH transcription factor families were presumed to play a role in the metabolic flux in the anthocyanin and proanthocyanidin biosynthetic pathway. The expression model of translational initiation factor, ribosomal proteins and SKP1-CUL1-F-box protein complex related genes suggested an important role for translational and post-translational network in anthocyanin biosynthesis. In addition, pathway analysis indicated that light reaction or photo destruction might be an important external cause for floral color determination in lotus.ConclusionsIn this study, it is supposed that the natural lotus mutant 'Da Sajin' may have originated from a red-flowered ancestor. Partial loss of anthocyanin pigments in petals may result from metabolic disorder caused by light destruction. This disorder is mainly regulated at post translation and translation level, resulting in a non-inherited phenotype. These results contribute to an improved understanding of anthocyanin metabolism in lotus, and indicate that the translational and post-translational regulatory network determines the metabolic flux of anthocyanins and proanthocyanidins under specific environmental conditions.

Dataset Information

Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions.

Publications

Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions.

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