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 language | English (US) |
|---|---|
| Pages (from-to) | 1048-1064 |
| Number of pages | 17 |
| Journal | iScience |
| Volume | 19 |
| DOIs | |
| State | Published - Sep 27 2019 |
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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 journal › Article
}
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 -