Plana-Bonamaisó Anna, López-Begines Santiago, Fernández-Justel David, Junza Alexandra, Soler-Tapia Ariadna, Andilla Jordi, Loza-Alvarez Pablo, Rosa Jose Luis, Miralles Esther, Casals Isidre, Yanes Oscar, de la Villa Pedro, Buey Ruben M, Méndez Ana
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.
Elife. 2020 Apr 7;9:e56418. doi: 10.7554/eLife.56418.
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 Thr/Ser 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.
我们报告了视网膜中肌苷-5'-单磷酸脱氢酶1（IMPDH1）的体内调节情况。IMPDH1催化鸟嘌呤核苷酸从头合成中的限速步骤，影响GMP、GDP和GTP的细胞池。鸟嘌呤核苷酸稳态对于光感受器细胞至关重要，其中cGMP是光反应中的信号转导分子。IMPDH1突变会导致遗传性失明。我们揭示了Bateman结构域中视网膜IMPDH1在苏氨酸/丝氨酸处的光依赖性磷酸化，该磷酸化使该酶对GDP/GTP的变构抑制不敏感。当暴露于强光下时，活体小鼠视网膜中GTP和ATP的合成速率会增加；同时IMPDH1在外节层形成聚集体。抑制活体小鼠中的IMPDH活性会延迟视杆细胞质量的恢复。我们揭示了一种体内调节IMPDH1的新机制，这对于理解视网膜中的GTP稳态以及常染色体显性视网膜色素变性10（adRP10）中IMPDH1突变的发病机制很重要。
