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

  1. Anna Plana-Bonamaisó
  2. Santiago López-Begines
  3. David Fernández-Justel
  4. Alexandra Junza
  5. Ariadna Soler-Tapia
  6. Jordi Andilla
  7. Pablo Loza-Alvarez
  8. Jose Luis Rosa
  9. Esther Miralles
  10. Isidre Casals
  11. Oscar Yanes
  12. Pedro de la Villa
  13. Ruben M Buey
  14. Ana Méndez  Is a corresponding author
  1. University of Barcelona, Spain
  2. University of Salamanca, Spain
  3. CIBERDEM, Spain
  4. ICFO-Institut de Ciencies Fotoniques, Spain
  5. Universitat de Barcelona, Spain
  6. University of Alcalá de Henares, School of Medicine, Spain
  7. 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.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Anna Plana-Bonamaisó

    Department of Physiological Sciences, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  2. Santiago López-Begines

    Department of Physiological Sciences, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8809-8919
  3. David Fernández-Justel

    Metabolic Engineering Group. Department of Microbiology and Genetics., University of Salamanca, Salamanca, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5728-2756
  4. Alexandra Junza

    CIBERDEM, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Ariadna Soler-Tapia

    Department of Physiological Sciences, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  6. Jordi Andilla

    The Barcelona Institute of Science and Technology, ICFO-Institut de Ciencies Fotoniques, Castelldefels, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Pablo Loza-Alvarez

    The Barcelona Institute of Science and Technology, ICFO-Institut de Ciencies Fotoniques, Castelldefels, Spain
    Competing interests
    The authors declare that no competing interests exist.
  8. Jose Luis Rosa

    Department of Physiological Sciences, University of Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  9. Esther Miralles

    Centros Científicos y Tecnológicos de la UB, CCiT-UB, Universitat de Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  10. Isidre Casals

    Centros Científicos y Tecnológicos de la UB, CCiT-UB, Universitat de Barcelona, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  11. Oscar Yanes

    CIBERDEM, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  12. Pedro de la Villa

    Department of System Biology, University of Alcalá de Henares, School of Medicine, Alcalá de Henares, Spain
    Competing interests
    The authors declare that no competing interests exist.
  13. Ruben M Buey

    Microbiología y Genética, Universidad de Salamanca, Salamanca, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1263-0221
  14. Ana Méndez

    Department of Physiological Sciences, University of Barcelona, Barcelona, Spain
    For correspondence
    mendezzu@idibell.cat
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6393-1644

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).

Reviewing Editor

  1. Constance L Cepko, Harvard Medical School, United States

Publication history

  1. Received: February 26, 2020
  2. Accepted: March 30, 2020
  3. Accepted Manuscript published: April 7, 2020 (version 1)
  4. Version of Record published: April 22, 2020 (version 2)

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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  1. Anna Plana-Bonamaisó
  2. Santiago López-Begines
  3. David Fernández-Justel
  4. Alexandra Junza
  5. Ariadna Soler-Tapia
  6. Jordi Andilla
  7. Pablo Loza-Alvarez
  8. Jose Luis Rosa
  9. Esther Miralles
  10. Isidre Casals
  11. Oscar Yanes
  12. Pedro de la Villa
  13. Ruben M Buey
  14. Ana Méndez
(2020)
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

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