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

Inosine monophosphate dehydrogenase (IMPDH) is a key regulatory enzyme in the de novo synthesis of the purine base guanine. Dominant mutations in human IMPDH1 cause photoreceptor degeneration for reasons that are unknown. Here, we sought to provide some foundational information on Impdh1a in the zeb...

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Autores principales: Cleghorn, Whitney M., Burrell, Anika L., Giarmarco, Michelle M., Brock, Daniel C., Wang, Yekai, Chambers, Zachary S., Du, Jianhai, Kollman, Justin M., Brockerhoff, Susan E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688572/
https://www.ncbi.nlm.nih.gov/pubmed/34813793
http://dx.doi.org/10.1016/j.jbc.2021.101441
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author Cleghorn, Whitney M.
Burrell, Anika L.
Giarmarco, Michelle M.
Brock, Daniel C.
Wang, Yekai
Chambers, Zachary S.
Du, Jianhai
Kollman, Justin M.
Brockerhoff, Susan E.
author_facet Cleghorn, Whitney M.
Burrell, Anika L.
Giarmarco, Michelle M.
Brock, Daniel C.
Wang, Yekai
Chambers, Zachary S.
Du, Jianhai
Kollman, Justin M.
Brockerhoff, Susan E.
author_sort Cleghorn, Whitney M.
collection PubMed
description Inosine monophosphate dehydrogenase (IMPDH) is a key regulatory enzyme in the de novo synthesis of the purine base guanine. Dominant mutations in human IMPDH1 cause photoreceptor degeneration for reasons that are unknown. Here, we sought to provide some foundational information on Impdh1a in the zebrafish retina. We found that in zebrafish, gene subfunctionalization due to ancestral duplication resulted in a predominant retinal variant expressed exclusively in rod and cone photoreceptors. This variant is structurally and functionally similar to the human IMPDH1 retinal variant and shares a reduced sensitivity to GTP-mediated inhibition. We also demonstrated that Impdh1a forms prominent protein filaments in vitro and in vivo in both rod and cone photoreceptor cell bodies, synapses, and to a lesser degree, in outer segments. These filaments changed length and cellular distribution throughout the day consistent with diurnal changes in both mRNA and protein levels. The loss of Impdh1a resulted in a substantial reduction of guanine levels, although cellular morphology and cGMP levels remained normal. Our findings demonstrate a significant role for IMPDH1 in photoreceptor guanine production and provide fundamental new information on the details of this protein in the zebrafish retina.
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spelling pubmed-86885722021-12-30 A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells Cleghorn, Whitney M. Burrell, Anika L. Giarmarco, Michelle M. Brock, Daniel C. Wang, Yekai Chambers, Zachary S. Du, Jianhai Kollman, Justin M. Brockerhoff, Susan E. J Biol Chem Research Article Inosine monophosphate dehydrogenase (IMPDH) is a key regulatory enzyme in the de novo synthesis of the purine base guanine. Dominant mutations in human IMPDH1 cause photoreceptor degeneration for reasons that are unknown. Here, we sought to provide some foundational information on Impdh1a in the zebrafish retina. We found that in zebrafish, gene subfunctionalization due to ancestral duplication resulted in a predominant retinal variant expressed exclusively in rod and cone photoreceptors. This variant is structurally and functionally similar to the human IMPDH1 retinal variant and shares a reduced sensitivity to GTP-mediated inhibition. We also demonstrated that Impdh1a forms prominent protein filaments in vitro and in vivo in both rod and cone photoreceptor cell bodies, synapses, and to a lesser degree, in outer segments. These filaments changed length and cellular distribution throughout the day consistent with diurnal changes in both mRNA and protein levels. The loss of Impdh1a resulted in a substantial reduction of guanine levels, although cellular morphology and cGMP levels remained normal. Our findings demonstrate a significant role for IMPDH1 in photoreceptor guanine production and provide fundamental new information on the details of this protein in the zebrafish retina. American Society for Biochemistry and Molecular Biology 2021-11-20 /pmc/articles/PMC8688572/ /pubmed/34813793 http://dx.doi.org/10.1016/j.jbc.2021.101441 Text en © 2021 The Authors https://creativecommons.org/licenses/by-nc-nd/3.0/igo/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/igo/).
spellingShingle Research Article
Cleghorn, Whitney M.
Burrell, Anika L.
Giarmarco, Michelle M.
Brock, Daniel C.
Wang, Yekai
Chambers, Zachary S.
Du, Jianhai
Kollman, Justin M.
Brockerhoff, Susan E.
A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells
title A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells
title_full A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells
title_fullStr A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells
title_full_unstemmed A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells
title_short A highly conserved zebrafish IMPDH retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells
title_sort highly conserved zebrafish impdh retinal isoform produces the majority of guanine and forms dynamic protein filaments in photoreceptor cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688572/
https://www.ncbi.nlm.nih.gov/pubmed/34813793
http://dx.doi.org/10.1016/j.jbc.2021.101441
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