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.
Highlights
Mutations in inosine monophosphate dehydrogenase 1 (IMPDH1), the enzyme responsible for the first and rate-limiting step in GTP synthesis, are associated to severe forms of inherited blindness
We show that the predominant retinal splice form of IMPDH1 is phosphorylated at the Bateman domain (T159/S160) in response to light in vivo; and that this phosphorylation desensitizes the enzyme to GDP/GTP allosteric inhibition of catalytic activity in vitro
Residues Thr159 and Ser160 map within the cystathionine b-synthase (CBS) motif 1 of the Bateman domain, in close proximity to Asn198, Arg224 and Asp226 mutated in autosomal dominant Lebers Congenital Amaurosis (adLCA) or adRP10 (Figure 2C–D), and are directly involved in the binding of purine nucleotides at the allosteric nucleotide binding site 1 (FernandezJustel et al, 2019)
Summary
Mutations in inosine monophosphate dehydrogenase 1 (IMPDH1), the enzyme responsible for the first and rate-limiting step in GTP synthesis, are associated to severe forms of inherited blindness. At least nine mutations have been associated to the RP10 form of autosomal dominant retinitis pigmentosa, that primarily manifests as night blindness and gradually progresses to loss of central vision: R224P (Kennan et al, 2002); D226N (Bowne et al, 2002); R231P (Grover et al, 2004); T116M, V268I, G324D, H372P (Bowne et al, 2006a); K238E and K238R (Wada et al, 2005). Together they account for about 1% of adRP cases (Sullivan et al, 2013).
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