Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions
- University of Barcelona, Spain
- University of Salamanca, Spain
- CIBERDEM, Spain
- ICFO-Institut de Ciencies Fotoniques, Spain
- Universitat de Barcelona, Spain
- University of Alcalá de Henares, School of Medicine, Spain
- Universidad de Salamanca, Spain
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.
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All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Santiago López-Begines
David Fernández-Justel
Funding
Ministerio de Economía y Competitividad (BFU2016-80583-R)
- Ana Méndez
Laser Lab Europe (654148)
- Pablo Loza-Alvarez
Fundación Ramón Areces (XVII Edition Rare Diseases)
- Ana Méndez
Fundacio La Marató (20141730)
- Jordi Andilla
- Pablo Loza-Alvarez
- Ana Méndez
Ministerio de Economía y Competitividad (BFU2016-79237-P)
- Ruben M Buey
Instituto de Salud Carlos III (PI18/00754)
- Pedro de la Villa
Junta de Castilla y León (Graduate student fellowship)
- David Fernández-Justel
Ministerio de Economía y Competitividad (SEV-2015-0522)
- Pablo Loza-Alvarez
Centres de Recerca de Catalunya (CERCA Institutional Support)
- Pablo Loza-Alvarez
- Ana Méndez
Fundació Privada Cellex (ICFO Institutional Support)
- Pablo Loza-Alvarez
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Pertaining to animal research, this study was conducted in accordance with the ARVO statement for the use of animals in ophthalmic and vision research and in compliance with acts 5/1995 and 214/1997 for the welfare of experimental animals of the autonomous community (Generalitat) of Catalonia; and approved by the ethics committee on animal experiments of the University of Barcelona (Generalitat Reference #9906, protocols Bell 216/17; 217/17 and 218/17).
Copyright
© 2020, Plana-Bonamaisó et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions
eLife 9:e56418.
https://doi.org/10.7554/eLife.56418
