IMP Dehydrogenase Type 1 Associates with Polyribosomes Translating Rhodopsin mRNA

Lizbeth Hedstrom,Sarah E Mortimer,Sara J Bowne,Dong Xu,Hoong Chuin Lim,Nobuko Hamaguchi,Dharia Mcgrew,Stephen P Daiger

doi:10.1074/jbc.m806143200

Lizbeth Hedstrom, Sarah E Mortimer + Show 6 more

Open Access

https://doi.org/10.1074/jbc.m806143200

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Abstract

IMP dehydrogenase (IMPDH) catalyzes the pivotal step in guanine nucleotide biosynthesis. Here we show that both IMPDH type 1 (IMPDH1) and IMPDH type 2 are associated with polyribosomes, suggesting that these housekeeping proteins have an unanticipated role in translation regulation. This interaction is mediated by the subdomain, a region of disputed function that is the site of mutations that cause retinal degeneration. The retinal isoforms of IMPDH1 also associate with polyribosomes. The most common disease-causing mutation, D226N, disrupts the polyribosome association of at least one retinal IMPDH1 isoform. Finally, we find that IMPDH1 is associated with polyribosomes containing rhodopsin mRNA. Because any perturbation of rhodopsin expression can trigger apoptosis in photoreceptor cells, these observations suggest a likely pathological mechanism for IMPDH1-mediated hereditary blindness. We propose that IMPDH coordinates the translation of a set of mRNAs, perhaps by modulating localization or degradation.

Highlights

IMP dehydrogenase (IMPDH)2 catalyzes the reaction that controls the entry of purines into the guanine nucleotide pool, and controls proliferation [1]
Mutations in the subdomain and the neighboring region of the barrel domain of IMPDH type 1 (IMPDH1) cause autosomal dominant retinitis pigmentosa and are associated with a more severe hereditary blindness, Leber congenital amaurosis (LCA) [23,24,25] (for the sake of simplicity, we will refer to the mutations of IMPDH1 that cause retinal disease as “RP-linked”; Fig. 1; mutations are designated according to the sequence of IMPDH1(514) [23, 25,26,27,28])
The anti-IMPDH antisera does not distinguish between IMPDH isozymes, IMPDH2 predominates in HeLa cells [37, 38]

Summary

Introduction

IMP dehydrogenase (IMPDH)2 catalyzes the reaction that controls the entry of purines into the guanine nucleotide pool, and controls proliferation [1]. The most common disease-causing mutation, D226N, disrupts the polyribosome association of at least one retinal IMPDH1 isoform. This observation suggests that the C-terminal extension blocks the nucleic acid-binding site, perhaps by interacting with the subdomain [22].

Results

Conclusion