Post-translational regulation of retinal IMPDH1 in vivo to adjust GTP synthesis to illumination conditions
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
Affiliations
Anna Plana-Bonamaisó
Department 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
Metabolic Engineering Group, Department of Microbiology and Genetics. University of Salamanca, Salamanca, Spain
Alexandra Junza
CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain; Metabolomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain
Ariadna Soler-Tapia
Department of Physiological Sciences, School of Medicine, Campus Universitari de Bellvitge, University of Barcelona, Barcelona, Spain
Jordi Andilla
ICFO-Institut de Ciencies Fotoniques, The Barcelona Institute of Science and Technology, Castelldefels, Spain
Pablo Loza-Alvarez
ICFO-Institut de Ciencies Fotoniques, The Barcelona Institute of Science and Technology, Castelldefels, Spain
Jose Luis Rosa
Department 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, Spain
Esther Miralles
Centres Cientifics i Tecnològics (CCiTUB), University of Barcelona, Parc Científic de Barcelona, Barcelona, Spain
Isidre Casals
Centres Cientifics i Tecnològics (CCiTUB), University of Barcelona, Parc Científic de Barcelona, Barcelona, Spain
Oscar Yanes
CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM), Madrid, Spain; Metabolomics Platform, IISPV, Department of Electronic Engineering, Universitat Rovira i Virgili, Tarragona, Spain
Pedro de la Villa
Physiology Unit, Dept of Systems Biology, School of Medicine, University of Alcalá, Madrid, Spain; Visual Neurophysiology Group-IRYCIS, Madrid, Spain
Department 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, Spain
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.
