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

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Standard

HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response. / Rotblat, Barak; Southwell, Amber L; Ehrnhoefer, Dagmar E; Skotte, Niels H; Metzler, Martina; Franciosi, Sonia; Leprivier, Gabriel; Somasekharan, Syam Prakash; Barokas, Adi; Deng, Yu; Tang, Tiffany; Mathers, Joan; Cetinbas, Naniye; Daugaard, Mads; Kwok, Brian; Li, Liheng; Carnie, Christopher J; Fink, Dieter; Nitsch, Roberto; Galpin, Jason D; Ahern, Christopher A; Melino, Gerry; Penninger, Josef M; Hayden, Michael R; Sorensen, Poul H.

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

Harvard

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

APA

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

Vancouver

Rotblat B, Southwell AL, Ehrnhoefer DE, Skotte NH, Metzler M, Franciosi S et al. 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. 2014 Feb 25;111(8):3032-7. https://doi.org/10.1073/pnas.1314421111

Author

Rotblat, Barak ; Southwell, Amber L ; Ehrnhoefer, Dagmar E ; Skotte, Niels H ; Metzler, Martina ; Franciosi, Sonia ; Leprivier, Gabriel ; Somasekharan, Syam Prakash ; Barokas, Adi ; Deng, Yu ; Tang, Tiffany ; Mathers, Joan ; Cetinbas, Naniye ; Daugaard, Mads ; Kwok, Brian ; Li, Liheng ; Carnie, Christopher J ; Fink, Dieter ; Nitsch, Roberto ; Galpin, Jason D ; Ahern, Christopher A ; Melino, Gerry ; Penninger, Josef M ; Hayden, Michael R ; Sorensen, Poul H. / HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 8. pp. 3032-7.

Bibtex

@article{c85f8e10e2db4905bc88c60d03446a35,
title = "HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response",
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.",
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",
author = "Barak Rotblat and Southwell, {Amber L} and Ehrnhoefer, {Dagmar E} and Skotte, {Niels H} and Martina Metzler and Sonia Franciosi and Gabriel Leprivier and Somasekharan, {Syam Prakash} and Adi Barokas and Yu Deng and Tiffany Tang and Joan Mathers and Naniye Cetinbas and Mads Daugaard and Brian Kwok and Liheng Li and Carnie, {Christopher J} and Dieter Fink and Roberto Nitsch and Galpin, {Jason D} and Ahern, {Christopher A} and Gerry Melino and Penninger, {Josef M} and Hayden, {Michael R} and Sorensen, {Poul H}",
year = "2014",
month = feb,
day = "25",
doi = "10.1073/pnas.1314421111",
language = "English",
volume = "111",
pages = "3032--7",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "The National Academy of Sciences of the United States of America",
number = "8",

}

RIS

TY - JOUR

T1 - HACE1 reduces oxidative stress and mutant Huntingtin toxicity by promoting the NRF2 response

AU - Rotblat, Barak

AU - Southwell, Amber L

AU - Ehrnhoefer, Dagmar E

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

PY - 2014/2/25

Y1 - 2014/2/25

N2 - 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.

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.

KW - Animals

KW - Blotting, Western

KW - Cell Fractionation

KW - Corpus Striatum

KW - DNA Primers

KW - Fluorescent Antibody Technique

KW - HEK293 Cells

KW - Humans

KW - Huntington Disease

KW - Mice

KW - NF-E2-Related Factor 2

KW - Nerve Tissue Proteins

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

C2 - 24516159

VL - 111

SP - 3032

EP - 3037

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

SN - 0027-8424

IS - 8

ER -

ID: 153451607