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.
authors: Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada V5Z 1L3.
authors: Barak
authors: B
authors: Rotblat
authors: Amber L
authors: AL
authors: Southwell
authors: Dagmar E
authors: DE
authors: Ehrnhoefer
authors: Niels H
authors: NH
authors: Skotte
authors: Martina
authors: M
authors: Metzler
authors: Sonia
authors: S
authors: Franciosi
authors: Gabriel
authors: G
authors: Leprivier
authors: Syam Prakash
authors: SP
authors: Somasekharan
authors: Adi
authors: A
authors: Barokas
authors: Yu
authors: Y
authors: Deng
authors: Tiffany
authors: T
authors: Tang
authors: Joan
authors: J
authors: Mathers
authors: Naniye
authors: N
authors: Cetinbas
authors: Mads
authors: M
authors: Daugaard
authors: Brian
authors: B
authors: Kwok
authors: Liheng
authors: L
authors: Li
authors: Christopher J
authors: CJ
authors: Carnie
authors: Dieter
authors: D
authors: Fink
authors: Roberto
authors: R
authors: Nitsch
authors: Jason D
authors: JD
authors: Galpin
authors: Christopher A
authors: CA
authors: Ahern
authors: Gerry
authors: G
authors: Melino
authors: Josef M
authors: JM
authors: Penninger
authors: Michael R
authors: MR
authors: Hayden
authors: Poul H
authors: PH
authors: Sorensen
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002458:Cell Fractionation; D003342:Corpus Striatum / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D017931:DNA Primers; C086055:HTT protein, human; D000071058:Huntingtin Protein; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; C497506:HACE1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: ROS; aging; glutathione; transcription factor