Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions
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 c...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/56418 |
| _version_ | 1828384584066138112 |
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| author | Anna Plana-Bonamaisó Santiago López-Begines David Fernández-Justel Alexandra Junza Ariadna Soler-Tapia Jordi Andilla Pablo Loza-Alvarez Jose Luis Rosa Esther Miralles Isidre Casals Oscar Yanes Pedro de la Villa Ruben M Buey Ana Méndez |
| author_facet | Anna Plana-Bonamaisó Santiago López-Begines David Fernández-Justel Alexandra Junza Ariadna Soler-Tapia Jordi Andilla Pablo Loza-Alvarez Jose Luis Rosa Esther Miralles Isidre Casals Oscar Yanes Pedro de la Villa Ruben M Buey Ana Méndez |
| author_sort | Anna Plana-Bonamaisó |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T05:05:48Z |
| format | Article |
| id | doaj.art-0bb5adc61dcb4789b7eeb46936f8f9d9 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T05:05:48Z |
| publishDate | 2020-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-0bb5adc61dcb4789b7eeb46936f8f9d92022-12-22T02:01:15ZengeLife Sciences Publications LtdeLife2050-084X2020-04-01910.7554/eLife.56418Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditionsAnna Plana-Bonamaisó0Santiago López-Begines1https://orcid.org/0000-0001-8809-8919David Fernández-Justel2https://orcid.org/0000-0001-5728-2756Alexandra Junza3Ariadna Soler-Tapia4Jordi Andilla5Pablo Loza-Alvarez6Jose Luis Rosa7Esther Miralles8Isidre Casals9Oscar Yanes10Pedro de la Villa11Ruben M Buey12https://orcid.org/0000-0003-1263-0221Ana Méndez13https://orcid.org/0000-0001-6393-1644Department of Physiological Sciences, School of Medicine, Campus Universitari de Bellvitge, University of Barcelona, Barcelona, Spain; Institut de Neurociències, Campus Universitari de Bellvitge, University of Barcelona, Barcelona, SpainDepartment of Physiological Sciences, School of Medicine, Campus Universitari de Bellvitge, University of Barcelona, Barcelona, SpainMetabolic Engineering Group, Department of Microbiology and Genetics. University of Salamanca, Salamanca, SpainCIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain; Metabolomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, SpainDepartment of Physiological Sciences, School of Medicine, Campus Universitari de Bellvitge, University of Barcelona, Barcelona, SpainICFO-Institut de Ciencies Fotoniques, The Barcelona Institute of Science and Technology, Castelldefels, SpainICFO-Institut de Ciencies Fotoniques, The Barcelona Institute of Science and Technology, Castelldefels, SpainDepartment of Physiological Sciences, School of Medicine, Campus Universitari de Bellvitge, University of Barcelona, Barcelona, Spain; Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Campus Universitari de Bellvitge, University of Barcelona, Barcelona, SpainCentres Cientifics i Tecnològics (CCiTUB), University of Barcelona, Parc Científic de Barcelona, Barcelona, SpainCentres Cientifics i Tecnològics (CCiTUB), University of Barcelona, Parc Científic de Barcelona, Barcelona, SpainCIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain; Metabolomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, SpainPhysiology Unit, Dept of Systems Biology, School of Medicine, University of Alcalá, Madrid, Spain; Visual Neurophysiology Group-IRYCIS, Madrid, SpainMetabolic Engineering Group, Department of Microbiology and Genetics. University of Salamanca, Salamanca, SpainDepartment of Physiological Sciences, School of Medicine, Campus Universitari de Bellvitge, University of Barcelona, Barcelona, Spain; Institut de Neurociències, Campus Universitari de Bellvitge, University of Barcelona, Barcelona, Spain; Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Campus Universitari de Bellvitge, University of Barcelona, Barcelona, SpainWe 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.https://elifesciences.org/articles/56418retinal dystrophyphotoreceptor metabolismIMPDH1enzymologyphotoreceptor physiologycGMP |
| spellingShingle | Anna Plana-Bonamaisó Santiago López-Begines David Fernández-Justel Alexandra Junza Ariadna Soler-Tapia Jordi Andilla Pablo Loza-Alvarez Jose Luis Rosa Esther Miralles Isidre Casals Oscar Yanes Pedro de la Villa Ruben M Buey Ana Méndez Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions eLife retinal dystrophy photoreceptor metabolism IMPDH1 enzymology photoreceptor physiology cGMP |
| title | Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions |
| title_full | Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions |
| title_fullStr | Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions |
| title_full_unstemmed | Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions |
| title_short | Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions |
| title_sort | post translational regulation of retinal impdh1 in vivo to adjust gtp synthesis to illumination conditions |
| topic | retinal dystrophy photoreceptor metabolism IMPDH1 enzymology photoreceptor physiology cGMP |
| url | https://elifesciences.org/articles/56418 |
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