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 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.

A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells

“…3 and 4 ). This is consistent with recent findings in mice and zebrafish ( 22 , 36 , 47 ) although Impdh filaments, as measured by the appearance of aggregates, were only detected in mouse photoreceptors after exposure to bright light and then only in outer segments and not elsewhere in the cell ( 22 ). This increase in filaments within the outer segment correlated with elevated cGMP synthesis in the whole retina and led Plana-Bonamaisó et al.…”

“…This increase in filaments within the outer segment correlated with elevated cGMP synthesis in the whole retina and led Plana-Bonamaisó et al. ( 22 ) to propose that filaments in photoreceptor outer segments are required for continued cGMP production during phototransduction. Recent work with the human retinal variant and our work presented here on the zebrafish retinal variant ( Fig.…”

“…A recent study examining the role of endogenous IMPDH1 in mouse retina indicated a role for the enzyme in cGMP synthesis during prolonged bright light. This response correlated with enzyme phosphorylation and filament formation ( 22 ). Mutations that disrupt normal cGMP metabolism in photoreceptors cause cell degeneration and blindness ( 23 ).…”

Specialization of the photoreceptor transcriptome bySrrm3-dependent microexons is required for outer segment maintenance and vision

“…We identified RetMIC-containing genes that localize to the cilia basal body and transition zone ( POC1B, ARL6, CC2D2A 23 – 25 ), where they control ciliogenesis and vesicle anchoring to the OS microtubule axoneme. Others regulate OS disks morphogenesis ( PROM1 26 ), PR homeostasis ( IMPDH1 27 ), are involved in anterograde and retrograde transport ( IFT88, DYNC2H1, KIF1B 28,29 ) or are part of the centrosomal complex ( RPGRIP1L 30 ) (Fig. 1G).…”

Photoreceptor metabolic reprogramming: current understanding and therapeutic implications

“…These mutations disrupt the physiologic hydrolysis of cGMP to GMP 42 . Interestingly, purine synthesis has also been reported to be regulated by inosine monophosphate dehydrogenase 1 ( IMPDH1 ) and the presence of light 43 , and mutations in IMPDH1 result in nonsyndromic IRDs 14 , 43 . Isolated ophthalmic manifestations of these genetic mutations emphasize the importance of maintaining the outer retinal metabolic balance for PR survival.…”