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Updated: Feb 1, 2026
Production and Detection of Reactive Oxygen Species ROS in Cancers
Published on: November 21, 2011
High-mobility group box 1 links sensing of reactive oxygen species by huntingtin to its nuclear entry
Susie Son1, Laura E Bowie1, Tamara Maiuri1
1From the Department of Biochemistry and Biomedical Research, McMaster University, Hamilton, Ontario L8S 4L8, Canada.
Insights
High-mobility group box 1 (HMGB1) protein interacts with huntingtin, facilitating its nuclear entry during oxidative stress. This interaction is key to understanding Huntington's disease onset and progression.
Area of Science:
- Neurobiology
- Molecular Biology
- Genetics
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by CAG DNA expansion in the HTT gene.
- Mutant huntingtin protein accumulation in cell nuclei is a hallmark of HD.
- Huntingtin release from the endoplasmic reticulum and nuclear entry are regulated by oxidative stress.
Purpose of the Study:
- To identify proteins interacting with huntingtin's nuclear localization signal (NLS).
- To elucidate the role of identified interactors in huntingtin's nuclear transport during oxidative stress.
- To understand the mechanism linking reactive oxygen species (ROS) to Huntington's disease pathogenesis.
Main Methods:
- Protein-protein interaction studies using human fibroblasts.
- Correlation analysis of nuclear HMGB1 and huntingtin levels.
- Investigation of HMGB1 interaction with huntingtin's N17 region under ROS conditions.
Main Results:
- High-mobility group box 1 (HMGB1) identified as an interactor of huntingtin's proline-tyrosine nuclear localization signal (PY-NLS).
- Nuclear HMGB1 levels positively correlate with nuclear huntingtin levels in HD and normal cells.
- HMGB1 interaction with huntingtin's N17 region is enhanced by ROS and phosphorylation.
Conclusions:
- HMGB1 acts as a crucial mediator for huntingtin's nuclear entry during ROS stress.
- The HMGB1-huntingtin interaction relays ROS sensing to nuclear transport.
- ROS-induced HMGB1 interaction may trigger nuclear accumulation of mutant huntingtin in HD.
Abstract:
Huntington's disease (HD) is a neurodegenerative, age-onset disorder caused by a CAG DNA expansion in exon 1 of the HTT gene, resulting in a polyglutamine expansion in the huntingtin protein. Nuclear accumulation of mutant huntingtin is a hallmark of HD, resulting in elevated mutant huntingtin levels in cell nuclei. Huntingtin is normally retained at the endoplasmic reticulum via its N17 amphipathic α-helix domain but is released by oxidation of Met-8 during reactive oxygen species (ROS) stress. Huntingtin enters the nucleus via an importin β1- and 2-dependent proline-tyrosine nuclear localization signal (PY-NLS), which has a unique intervening sequence in huntingtin. Here, we have identified the high-mobility group box 1 (HMGB1) protein as an interactor of the intervening sequence within the PY-NLS. Nuclear levels of HMGB1 positively correlated with varying levels of nuclear huntingtin in both HD and normal human fibroblasts. We also found that HMGB1 interacts with the huntingtin N17 region and that this interaction is enhanced by the presence of ROS and phosphorylation of critical serine residues in the N17 region. We conclude that HMGB1 is a huntingtin N17/PY-NLS ROS-dependent interactor, and this protein bridging is essential for relaying ROS sensing by huntingtin to its nuclear entry during ROS stress. ROS may therefore be a critical age-onset stress that triggers nuclear accumulation of mutant huntington in Huntington's disease.
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