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
SN - 0027-8424
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
IS - 8
ER -
