HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Barak Rotblat; Amber L Southwell; Dagmar E Ehrnhoefer; Niels H Skotte; Martina Metzler; Sonia Franciosi; Gabriel Leprivier; Syam Prakash Somasekharan; Adi Barokas; Yu Deng; Tiffany Tang; Joan Mathers; Naniye Cetinbas; Mads Daugaard; Brian Kwok; Liheng Li; Christopher J Carnie; Dieter Fink; Roberto Nitsch; Jason D Galpin; Christopher A Ahern; Gerry Melino; Josef M Penninger; Michael R Hayden; Poul H Sorensen

doi:10.1073/pnas.1314421111

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Barak Rotblat, Amber L Southwell, Dagmar E Ehrnhoefer, Niels H Skotte, Martina Metzler, Sonia Franciosi, Gabriel Leprivier, Syam Prakash Somasekharan, Adi Barokas, Yu Deng, Tiffany Tang, Joan Mathers, Naniye Cetinbas, Mads Daugaard, Brian Kwok, Liheng Li, Christopher J Carnie, Dieter Fink, Roberto Nitsch, Jason D GalpinChristopher A Ahern, Gerry Melino, Josef M Penninger, Michael R Hayden, Poul H Sorensen

51 Citations (Scopus)

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.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	8
Pages (from-to)	3032-7
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1314421111
Publication status	Published - 25 Feb 2014
Externally published	Yes

Keywords

Animals
Blotting, Western
Cell Fractionation
Corpus Striatum
DNA Primers
Fluorescent Antibody Technique
HEK293 Cells
Humans
Huntington Disease
Mice
NF-E2-Related Factor 2
Nerve Tissue Proteins
Oxidative Stress
Reactive Oxygen Species
Real-Time Polymerase Chain Reaction
Ubiquitin-Protein Ligases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Rotblat, B., Southwell, A. L., Ehrnhoefer, D. E., Skotte, N. H., Metzler, M., Franciosi, S., Leprivier, G., Somasekharan, S. P., Barokas, A., Deng, Y., Tang, T., Mathers, J., Cetinbas, N., Daugaard, M., Kwok, B., Li, L., Carnie, C. J., Fink, D., Nitsch, R., ... Sorensen, P. H. (2014). HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response. Proceedings of the National Academy of Sciences of the United States of America, 111(8), 3032-7. https://doi.org/10.1073/pnas.1314421111

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response. / Rotblat, Barak; Southwell, Amber L; Ehrnhoefer, Dagmar E et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 8, 25.02.2014, p. 3032-7.

Research output: Contribution to journal › Journal article › Research › peer-review

Rotblat, B, Southwell, AL, Ehrnhoefer, DE, Skotte, NH, Metzler, M, Franciosi, S, Leprivier, G, Somasekharan, SP, Barokas, A, Deng, Y, Tang, T, Mathers, J, Cetinbas, N, Daugaard, M, Kwok, B, Li, L, Carnie, CJ, Fink, D, Nitsch, R, Galpin, JD, Ahern, CA, Melino, G, Penninger, JM, Hayden, MR & Sorensen, PH 2014, 'HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 8, pp. 3032-7. https://doi.org/10.1073/pnas.1314421111

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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.",

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AU - Skotte, Niels H

AU - Metzler, Martina

AU - Franciosi, Sonia

AU - Leprivier, Gabriel

AU - Somasekharan, Syam Prakash

AU - Barokas, Adi

AU - Deng, Yu

AU - Tang, Tiffany

AU - Mathers, Joan

AU - Cetinbas, Naniye

AU - Daugaard, Mads

AU - Kwok, Brian

AU - Li, Liheng

AU - Carnie, Christopher J

AU - Fink, Dieter

AU - Nitsch, Roberto

AU - Galpin, Jason D

AU - Ahern, Christopher A

AU - Melino, Gerry

AU - Penninger, Josef M

AU - Hayden, Michael R

AU - Sorensen, Poul H

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AB - 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.

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KW - Huntington Disease

KW - Mice

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KW - Oxidative Stress

KW - Reactive Oxygen Species

KW - Real-Time Polymerase Chain Reaction

KW - Ubiquitin-Protein Ligases

U2 - 10.1073/pnas.1314421111

DO - 10.1073/pnas.1314421111

M3 - Journal article

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SN - 0027-8424

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 8

ER -

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

Abstract

Keywords

UN SDGs

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