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

Joun Park, Yi Zhu, Xianzun Tao, Jennifer M. Brazill, Chong Li, Stefan Wuchty, R. Grace Zhai

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1048-1064
Number of pages17
JournaliScience
Volume19
DOIs
StatePublished - Sep 27 2019

Fingerprint

Nicotinamide-Nucleotide Adenylyltransferase
Alternative Splicing
MicroRNAs
RNA Precursors
Drosophila
Neurodegenerative Diseases
Protein Isoforms
Homeostasis
Maintenance
Messenger RNA
Enzymes

Keywords

  • Biological Sciences
  • Cell Biology
  • Molecular Biology

ASJC Scopus subject areas

  • General

Cite this

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.

In: iScience, Vol. 19, 27.09.2019, p. 1048-1064.

Research output: Contribution to journalArticle

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. In: iScience. 2019 ; Vol. 19. pp. 1048-1064.
@article{304697ce02f24f698fc59cbfd0fdf07c,
title = "MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing",
abstract = "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.",
keywords = "Biological Sciences, Cell Biology, Molecular Biology",
author = "Joun Park and Yi Zhu and Xianzun Tao and Brazill, {Jennifer M.} and Chong Li and Stefan Wuchty and Zhai, {R. Grace}",
year = "2019",
month = "9",
day = "27",
doi = "10.1016/j.isci.2019.08.052",
language = "English (US)",
volume = "19",
pages = "1048--1064",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - MicroRNA miR-1002 Enhances NMNAT-Mediated Stress Response by Modulating Alternative Splicing

AU - Park, Joun

AU - Zhu, Yi

AU - Tao, Xianzun

AU - Brazill, Jennifer M.

AU - Li, Chong

AU - Wuchty, Stefan

AU - Zhai, R. Grace

PY - 2019/9/27

Y1 - 2019/9/27

N2 - 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.

AB - 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.

KW - Biological Sciences

KW - Cell Biology

KW - Molecular Biology

UR - http://www.scopus.com/inward/record.url?scp=85072024982&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072024982&partnerID=8YFLogxK

U2 - 10.1016/j.isci.2019.08.052

DO - 10.1016/j.isci.2019.08.052

M3 - Article

AN - SCOPUS:85072024982

VL - 19

SP - 1048

EP - 1064

JO - iScience

JF - iScience

SN - 2589-0042

ER -