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MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing

Understanding endogenous regulation of stress resistance and homeostasis maintenance is critical to developing neuroprotective therapies. Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved essential enzyme that confers extraordinary protection and stress resistance in many neurod...

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Autores principales: Park, Joun, Zhu, Yi, Tao, Xianzun, Brazill, Jennifer M., Li, Chong, Wuchty, Stefan, Zhai, R. Grace
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745518/
https://www.ncbi.nlm.nih.gov/pubmed/31522116
http://dx.doi.org/10.1016/j.isci.2019.08.052
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author Park, Joun
Zhu, Yi
Tao, Xianzun
Brazill, Jennifer M.
Li, Chong
Wuchty, Stefan
Zhai, R. Grace
author_facet Park, Joun
Zhu, Yi
Tao, Xianzun
Brazill, Jennifer M.
Li, Chong
Wuchty, Stefan
Zhai, R. Grace
author_sort Park, Joun
collection PubMed
description Understanding endogenous regulation of stress resistance and homeostasis maintenance is critical to developing neuroprotective therapies. Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved essential enzyme that confers extraordinary protection and stress resistance in many neurodegenerative disease models. Drosophila Nmnat is alternatively spliced to two mRNA variants, RA and RB. RB translates to protein isoform PD with robust protective activity and is upregulated upon stress to confer enhanced neuroprotection. The mechanisms regulating the alternative splicing and stress response of NMNAT remain unclear. We have discovered a Drosophila microRNA, dme-miR-1002, which promotes the splicing of NMNAT pre-mRNA to RB by disrupting a pre-mRNA stem-loop structure. NMNAT pre-mRNA is preferentially spliced to RA in basal conditions, whereas miR-1002 enhances NMNAT PD-mediated stress protection by binding via RISC component Argonaute1 to the pre-mRNA, facilitating the splicing switch to RB. These results outline a new process for microRNAs in regulating alternative splicing and modulating stress resistance.
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spelling pubmed-67455182019-09-19 MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing Park, Joun Zhu, Yi Tao, Xianzun Brazill, Jennifer M. Li, Chong Wuchty, Stefan Zhai, R. Grace iScience Article Understanding endogenous regulation of stress resistance and homeostasis maintenance is critical to developing neuroprotective therapies. Nicotinamide mononucleotide adenylyltransferase (NMNAT) is a conserved essential enzyme that confers extraordinary protection and stress resistance in many neurodegenerative disease models. Drosophila Nmnat is alternatively spliced to two mRNA variants, RA and RB. RB translates to protein isoform PD with robust protective activity and is upregulated upon stress to confer enhanced neuroprotection. The mechanisms regulating the alternative splicing and stress response of NMNAT remain unclear. We have discovered a Drosophila microRNA, dme-miR-1002, which promotes the splicing of NMNAT pre-mRNA to RB by disrupting a pre-mRNA stem-loop structure. NMNAT pre-mRNA is preferentially spliced to RA in basal conditions, whereas miR-1002 enhances NMNAT PD-mediated stress protection by binding via RISC component Argonaute1 to the pre-mRNA, facilitating the splicing switch to RB. These results outline a new process for microRNAs in regulating alternative splicing and modulating stress resistance. Elsevier 2019-08-30 /pmc/articles/PMC6745518/ /pubmed/31522116 http://dx.doi.org/10.1016/j.isci.2019.08.052 Text en © 2019 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Park, Joun
Zhu, Yi
Tao, Xianzun
Brazill, Jennifer M.
Li, Chong
Wuchty, Stefan
Zhai, R. Grace
MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing
title MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing
title_full MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing
title_fullStr MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing
title_full_unstemmed MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing
title_short MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing
title_sort microrna mir-1002 enhances nmnat-mediated stress response by modulating alternative splicing
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6745518/
https://www.ncbi.nlm.nih.gov/pubmed/31522116
http://dx.doi.org/10.1016/j.isci.2019.08.052
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