Journal article
HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response
Proceedings of the National Academy of Sciences - PNAS, Vol.111(8), pp.3032-3037
02/25/2014
DOI: 10.1073/pnas.1314421111
PMCID: PMC3939919
PMID: 24516159
Abstract
Oxidative stress is an important contributor to aging-associated diseases including cancer and neurodegeneration, and antioxidant stress responses are critical to limit manifestations of these diseases. We report that the tumor suppressor Homologous to the E6-AP Carboxyl Terminus domain and Ankyrin repeat containing E3 ubiquitin–protein ligase 1 (HACE1) promotes activity of the transcription factor, nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the antioxidative stress response. In Huntington disease patients, HACE1 is lost in the brain region most affected by the disease, namely the striatum, and restoring HACE1 functions in striatal cells expressing mutant Huntingtin protein provides protection against oxidative stress. Therefore, the tumor suppressor HACE1 is a new regulator of NRF2 and an emerging player in neurodegeneration.
Oxidative stress plays a key role in late onset diseases including cancer and neurodegenerative diseases such as Huntington disease. Therefore, uncovering regulators of the antioxidant stress responses is important for understanding the course of these diseases. Indeed, the nuclear factor erythroid 2-related factor 2 (NRF2), a master regulator of the cellular antioxidative stress response, is deregulated in both cancer and neurodegeneration. Similar to NRF2, the tumor suppressor Homologous to the E6-AP Carboxyl Terminus (HECT) domain and Ankyrin repeat containing E3 ubiquitin–protein ligase 1 (HACE1) plays a protective role against stress-induced tumorigenesis in mice, but its roles in the antioxidative stress response or its involvement in neurodegeneration have not been investigated. To this end we examined
Hace1
WT and KO mice and found that
Hace1
KO animals exhibited increased oxidative stress in brain and that the antioxidative stress response was impaired. Moreover, HACE1 was found to be essential for optimal NRF2 activation in cells challenged with oxidative stress, as HACE1 depletion resulted in reduced NRF2 activity, stability, and protein synthesis, leading to lower tolerance against oxidative stress triggers. Strikingly, we found a reduction of HACE1 levels in the striatum of Huntington disease patients, implicating HACE1 in the pathology of Huntington disease. Moreover, ectopic expression of HACE1 in striatal neuronal progenitor cells provided protection against mutant Huntingtin-induced redox imbalance and hypersensitivity to oxidative stress, by augmenting NRF2 functions. These findings reveal that the tumor suppressor HACE1 plays a role in the NRF2 antioxidative stress response pathway and in neurodegeneration.
Details
- Title: Subtitle
- HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response
- Creators
- Barak Rotblat - Department of Molecular OncologyAmber L Southwell - Centre for Molecular Medicine and TherapeuticsDagmar E Ehrnhoefer - Centre for Molecular Medicine and TherapeuticsNiels H Skotte - Centre for Molecular Medicine and TherapeuticsMartina Metzler - Centre for Molecular Medicine and TherapeuticsSonia Franciosi - Centre for Molecular Medicine and TherapeuticsGabriel Leprivier - Department of Molecular OncologySyam Prakash Somasekharan - Department of Molecular OncologyAdi Barokas - Department of Molecular OncologyYu Deng - Centre for Molecular Medicine and TherapeuticsTiffany Tang - Department of Molecular OncologyJoan Mathers - Department of Molecular OncologyNaniye Cetinbas - Department of Molecular OncologyMads Daugaard - Department of Molecular OncologyBrian Kwok - Department of Molecular OncologyLiheng Li - Department of Molecular OncologyChristopher J Carnie - Department of Molecular OncologyDieter Fink - Department of Molecular OncologyRoberto Nitsch - , 1030 ViennaJason D Galpin - Department of Molecular Physiology and Biophysics, Carver College of MedicineChristopher A Ahern - Department of Molecular Physiology and Biophysics, Carver College of MedicineGerry Melino - Medical Research Council, Toxicology UnitJosef M Penninger - , 1030 ViennaMichael R Hayden - Centre for Molecular Medicine and TherapeuticsPoul H Sorensen - Department of Molecular Oncology
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.111(8), pp.3032-3037
- DOI
- 10.1073/pnas.1314421111
- PMID
- 24516159
- PMCID
- PMC3939919
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- National Academy of Sciences
- Alternative title
- HACE1 augments NRF2 to protect against ROS
- Language
- English
- Date published
- 02/25/2014
- Academic Unit
- Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984065495502771
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