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Updated: May 3, 2026
Measurements of Physiological Stress Responses in C. Elegans
Published on: May 21, 2020
HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response
Barak Rotblat1, Amber L Southwell, Dagmar E Ehrnhoefer
1Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada V5Z 1L3.
Abstract:
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.
Insights
The tumor suppressor HACE1 is crucial for the antioxidant stress response and NRF2 activation. Its deficiency impairs cellular defense, and reduced levels are linked to Huntington disease pathology.
Area of Science:
- Cellular biology
- Neuroscience
- Oncology
Background:
- Oxidative stress is implicated in aging-related diseases like cancer and neurodegeneration.
- Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of cellular antioxidant responses.
- HACE1, a tumor suppressor, protects against stress-induced tumorigenesis but its role in oxidative stress and neurodegeneration is unknown.
Purpose of the Study:
- To investigate the role of HACE1 in the antioxidative stress response.
- To determine HACE1's involvement in neurodegeneration, specifically Huntington disease.
- To elucidate the relationship between HACE1, NRF2, and oxidative stress.
Main Methods:
- Comparison of wild-type and HACE1 knockout mice.
- Assessment of oxidative stress markers and antioxidant response in brain tissue.
- Analysis of NRF2 activity, stability, and protein synthesis upon HACE1 depletion.
- Measurement of HACE1 levels in Huntington disease patient striatum.
- Evaluation of HACE1's protective effect in neuronal progenitor cells against mutant Huntingtin.
Main Results:
- HACE1 knockout mice showed increased oxidative stress and impaired antioxidant response in the brain.
- HACE1 is essential for optimal NRF2 activation, stability, and synthesis under oxidative stress.
- Depletion of HACE1 reduced cellular tolerance to oxidative stress triggers.
- HACE1 levels were decreased in the striatum of Huntington disease patients.
- Ectopic HACE1 expression protected neuronal cells against mutant Huntingtin-induced redox imbalance by enhancing NRF2.
Conclusions:
- HACE1 plays a significant role in the NRF2-mediated antioxidative stress response pathway.
- HACE1 deficiency contributes to oxidative stress and is implicated in Huntington disease pathology.
- HACE1 represents a potential therapeutic target for neurodegenerative diseases and conditions involving oxidative stress.
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