An internal ribosomal entry site mediates redox-sensitive translation of Nrf2

Wenge Li, Nehal Thakor, Eugenia Y. Xu, Ying Huang, Chi Chen, Rong Yu, Martin Holcik, Ah Ng Kong

Research output: Contribution to journalArticle

69 Citations (Scopus)

Abstract

Nrf2 plays pivotal roles in coordinating the antioxidant response and maintaining redox homeostasis. Nrf2 expression is exquisitely regulated; Nrf2 expression is suppressed under unstressed conditions but strikingly induced under oxidative stress. Previous studies showed that stress-induced Nrf2 up-regulation results from both the inhibition of Nrf2 degradation and enhanced Nrf2 translation. In the present study, we elucidate the mechanism underlying translational control of Nrf2. An internal ribosomal entry site (IRES) was identified within the 5′ untranslated region of human Nrf2 mRNA. The IRESNrf2 contains a highly conserved 18S rRNA binding site (RBS) that is required for internal initiation. This IRESNrf2 also contains a hairpin structured inhibitory element (IE) located upstream of the RBS. Deletion of this IE remarkably enhanced translation. Significantly, treatment of cells with hydrogen peroxide (H2O2) and phyto-oxidant sulforaphane further stimulated IRESNrf2-mediated translation initiation despite the attenuation of global protein synthesis. Polyribosomal profile assay confirmed that endogenous Nrf2 mRNAs were recruited into polysomal fractions under oxidative stress conditions. Collectively, these data demonstrate that Nrf2 translation is suppressed under normal conditions and specifically enhanced upon oxidant exposure by internal initiation, and provide a mechanistic explanation for translational control of Nrf2 by oxidative stress.

Original languageEnglish (US)
Article numbergkp1048
Pages (from-to)778-788
Number of pages11
JournalNucleic Acids Research
Volume38
Issue number3
DOIs
StatePublished - Nov 24 2009
Externally publishedYes

Fingerprint

Oxidation-Reduction
Oxidative Stress
Oxidants
Binding Sites
Messenger RNA
5' Untranslated Regions
Hydrogen Peroxide
Homeostasis
Up-Regulation
Antioxidants
Proteins
sulforafan

ASJC Scopus subject areas

  • Genetics

Cite this

Li, W., Thakor, N., Xu, E. Y., Huang, Y., Chen, C., Yu, R., ... Kong, A. N. (2009). An internal ribosomal entry site mediates redox-sensitive translation of Nrf2. Nucleic Acids Research, 38(3), 778-788. [gkp1048]. https://doi.org/10.1093/nar/gkp1048

An internal ribosomal entry site mediates redox-sensitive translation of Nrf2. / Li, Wenge; Thakor, Nehal; Xu, Eugenia Y.; Huang, Ying; Chen, Chi; Yu, Rong; Holcik, Martin; Kong, Ah Ng.

In: Nucleic Acids Research, Vol. 38, No. 3, gkp1048, 24.11.2009, p. 778-788.

Research output: Contribution to journalArticle

Li, W, Thakor, N, Xu, EY, Huang, Y, Chen, C, Yu, R, Holcik, M & Kong, AN 2009, 'An internal ribosomal entry site mediates redox-sensitive translation of Nrf2', Nucleic Acids Research, vol. 38, no. 3, gkp1048, pp. 778-788. https://doi.org/10.1093/nar/gkp1048
Li, Wenge ; Thakor, Nehal ; Xu, Eugenia Y. ; Huang, Ying ; Chen, Chi ; Yu, Rong ; Holcik, Martin ; Kong, Ah Ng. / An internal ribosomal entry site mediates redox-sensitive translation of Nrf2. In: Nucleic Acids Research. 2009 ; Vol. 38, No. 3. pp. 778-788.
@article{ebc8f842c3a647d29c07158e5da9246f,
title = "An internal ribosomal entry site mediates redox-sensitive translation of Nrf2",
abstract = "Nrf2 plays pivotal roles in coordinating the antioxidant response and maintaining redox homeostasis. Nrf2 expression is exquisitely regulated; Nrf2 expression is suppressed under unstressed conditions but strikingly induced under oxidative stress. Previous studies showed that stress-induced Nrf2 up-regulation results from both the inhibition of Nrf2 degradation and enhanced Nrf2 translation. In the present study, we elucidate the mechanism underlying translational control of Nrf2. An internal ribosomal entry site (IRES) was identified within the 5′ untranslated region of human Nrf2 mRNA. The IRESNrf2 contains a highly conserved 18S rRNA binding site (RBS) that is required for internal initiation. This IRESNrf2 also contains a hairpin structured inhibitory element (IE) located upstream of the RBS. Deletion of this IE remarkably enhanced translation. Significantly, treatment of cells with hydrogen peroxide (H2O2) and phyto-oxidant sulforaphane further stimulated IRESNrf2-mediated translation initiation despite the attenuation of global protein synthesis. Polyribosomal profile assay confirmed that endogenous Nrf2 mRNAs were recruited into polysomal fractions under oxidative stress conditions. Collectively, these data demonstrate that Nrf2 translation is suppressed under normal conditions and specifically enhanced upon oxidant exposure by internal initiation, and provide a mechanistic explanation for translational control of Nrf2 by oxidative stress.",
author = "Wenge Li and Nehal Thakor and Xu, {Eugenia Y.} and Ying Huang and Chi Chen and Rong Yu and Martin Holcik and Kong, {Ah Ng}",
year = "2009",
month = "11",
day = "24",
doi = "10.1093/nar/gkp1048",
language = "English (US)",
volume = "38",
pages = "778--788",
journal = "Nucleic Acids Research",
issn = "0305-1048",
publisher = "Oxford University Press",
number = "3",

}

TY - JOUR

T1 - An internal ribosomal entry site mediates redox-sensitive translation of Nrf2

AU - Li, Wenge

AU - Thakor, Nehal

AU - Xu, Eugenia Y.

AU - Huang, Ying

AU - Chen, Chi

AU - Yu, Rong

AU - Holcik, Martin

AU - Kong, Ah Ng

PY - 2009/11/24

Y1 - 2009/11/24

N2 - Nrf2 plays pivotal roles in coordinating the antioxidant response and maintaining redox homeostasis. Nrf2 expression is exquisitely regulated; Nrf2 expression is suppressed under unstressed conditions but strikingly induced under oxidative stress. Previous studies showed that stress-induced Nrf2 up-regulation results from both the inhibition of Nrf2 degradation and enhanced Nrf2 translation. In the present study, we elucidate the mechanism underlying translational control of Nrf2. An internal ribosomal entry site (IRES) was identified within the 5′ untranslated region of human Nrf2 mRNA. The IRESNrf2 contains a highly conserved 18S rRNA binding site (RBS) that is required for internal initiation. This IRESNrf2 also contains a hairpin structured inhibitory element (IE) located upstream of the RBS. Deletion of this IE remarkably enhanced translation. Significantly, treatment of cells with hydrogen peroxide (H2O2) and phyto-oxidant sulforaphane further stimulated IRESNrf2-mediated translation initiation despite the attenuation of global protein synthesis. Polyribosomal profile assay confirmed that endogenous Nrf2 mRNAs were recruited into polysomal fractions under oxidative stress conditions. Collectively, these data demonstrate that Nrf2 translation is suppressed under normal conditions and specifically enhanced upon oxidant exposure by internal initiation, and provide a mechanistic explanation for translational control of Nrf2 by oxidative stress.

AB - Nrf2 plays pivotal roles in coordinating the antioxidant response and maintaining redox homeostasis. Nrf2 expression is exquisitely regulated; Nrf2 expression is suppressed under unstressed conditions but strikingly induced under oxidative stress. Previous studies showed that stress-induced Nrf2 up-regulation results from both the inhibition of Nrf2 degradation and enhanced Nrf2 translation. In the present study, we elucidate the mechanism underlying translational control of Nrf2. An internal ribosomal entry site (IRES) was identified within the 5′ untranslated region of human Nrf2 mRNA. The IRESNrf2 contains a highly conserved 18S rRNA binding site (RBS) that is required for internal initiation. This IRESNrf2 also contains a hairpin structured inhibitory element (IE) located upstream of the RBS. Deletion of this IE remarkably enhanced translation. Significantly, treatment of cells with hydrogen peroxide (H2O2) and phyto-oxidant sulforaphane further stimulated IRESNrf2-mediated translation initiation despite the attenuation of global protein synthesis. Polyribosomal profile assay confirmed that endogenous Nrf2 mRNAs were recruited into polysomal fractions under oxidative stress conditions. Collectively, these data demonstrate that Nrf2 translation is suppressed under normal conditions and specifically enhanced upon oxidant exposure by internal initiation, and provide a mechanistic explanation for translational control of Nrf2 by oxidative stress.

UR - http://www.scopus.com/inward/record.url?scp=77950352188&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77950352188&partnerID=8YFLogxK

U2 - 10.1093/nar/gkp1048

DO - 10.1093/nar/gkp1048

M3 - Article

C2 - 19934254

AN - SCOPUS:77950352188

VL - 38

SP - 778

EP - 788

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 3

M1 - gkp1048

ER -