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

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 I

SUBMITTER: Plana-Bonamaiso A 

PROVIDER: S-EPMC7176436 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature