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

• DOI: 10.7554/elife.56418
• Publication Date: 2020-04-07T12:00:15Z
• Authors: Anna Plana-Bonamaisó; Santiago López-Be...; David Fernández-J...; 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
• Keywords: 0301 basic medicine; IMPDH1; Light; QH301-705.5; Biochemical Phenomena; Science; enzymology; Homeòstasi; chemical biology; Retina; neuroscience; Mice; 03 medical and health sciences; Adenosine Triphosphate; IMP Dehydrogenase; Biochemistry and Chemical Biology; biochemistry; Animals; Homeostasis; Photoreceptor Cells; Biology (General); retinal dystrophy; Phosphorylation; mouse; Nucleotides; Q; R; photoreceptor physiology; photoreceptor metabolism; cGMP; Nucleòtids; Mice, Inbred C57BL; Gene Expression Regulation; Mutation; Medicine; Guanosine Triphosphate; Protein Processing, Post-Translational; Photic Stimulation

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.