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The ubiquitin-conjugating enzyme UbcM2 can regulate the stability and activity of the antioxidant transcription factor Nrf2.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2010 Jul 23; Vol. 285 (30), pp. 23064-74. Date of Electronic Publication: 2010 May 18. - Publication Year :
- 2010
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Abstract
- The transcription factor nuclear factor E2-related factor 2 (Nrf2) induces the expression of antioxidant gene products that neutralize reactive oxygen species and restore redox homeostasis. Nrf2 is constitutively degraded by the ubiquitin proteolytic system in unperturbed cells, but this turnover is arrested in response to oxidative stress, thereby leading to Nrf2 accumulation. Yet, a mechanistic understanding of how Nrf2 stabilization and transcriptional activation are coupled remains to be determined. We have discovered that the ubiquitin-conjugating enzyme UbcM2 is a novel regulator of Nrf2. Recombinant Nrf2 and UbcM2 form a complex upon alkylation of a non-catalytic cysteine in UbcM2, Cys-136. Substitution of this cysteine with a phenylalanine (C136F) to mimic cysteine oxidation/alkylation results in constitutive binding of UbcM2 to Nrf2 and an increased half-life of the transcription factor in vivo. We provide evidence that UbcM2 and Nrf2 form a nuclear complex utilizing the DNA binding, Neh1 domain, of Nrf2. Finally, we demonstrate that UbcM2 can enhance the transcriptional activity of endogenous Nrf2 and that Cys-136 and the active-site cysteine, Cys-145, jointly contribute to this regulation. Collectively, these data identify UbcM2 as a novel component of the Nrf2 regulatory circuit and position cysteine 136 as a putative redox sensor in this signaling pathway. This work implicates UbcM2 in the restoration of redox homeostasis following oxidative stress.
- Subjects :
- Amino Acid Sequence
Catalytic Domain
Cysteine metabolism
HeLa Cells
Homeostasis
Humans
Molecular Sequence Data
Oxidation-Reduction
Oxidative Stress
Protein Stability
Protein Structure, Tertiary
Transcriptional Activation
Ubiquitin metabolism
Ubiquitin-Conjugating Enzymes chemistry
NF-E2-Related Factor 2 chemistry
NF-E2-Related Factor 2 metabolism
Ubiquitin-Conjugating Enzymes metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 285
- Issue :
- 30
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20484052
- Full Text :
- https://doi.org/10.1074/jbc.M110.121913