High-mobility group box 1 links sensing of reactive oxygen species by huntingtin to its nuclear entry

Abstract

Edited by Ursula JakobHuntington'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 ␣-helix domain but is released by oxidation of Met-8 during reactive oxygen species (ROS) stress. Huntingtin enters the nucleus via an importin ␤1and 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.

Nrf2 Pathway in Huntington’s Disease (HD): What Is Its Role?

“…A clear bi-directional interaction between mHTT and OS in HD was demonstrated in different studies [ 64 ]. The OS plays a critical role in the nuclear accumulation of mHTT [ 65 ], inducing proteasomal dysfunction, facilitating mHTT aggregation, and, finally, neuronal death [ 66 ]. The involvement of OS in CAG expansion was described in somatic and embryonic mouse cells [ 67 , 68 ].…”

Investigating Crosstalk Among PTMs Provides Novel Insight Into the Structural Basis Underlying the Differential Effects of Nt17 PTMs on Mutant Httex1 Aggregation

“…Elevated levels of oxidative stress markers, including reactive oxygen species (ROS), were found in blood ( Chen et al, 2007 ) and postmortem brains of HD patients ( Polidori et al, 1999 ). Although there is no direct evidence establishing that M8 is oxidized, several studies have suggested that this could occur under oxidative stress conditions and that M8 oxidation could act as a sensor of ROS to regulate Htt phosphorylation and localization ( DiGiovanni et al, 2016 ; Son et al, 2019 ). Mitomi and colleagues ( Mitomi et al, 2012 ) showed, using hydrogen peroxide (H 2 O 2 ) mediated oxidizing conditions in vitro , that oxidation at M8 occurs only post-aggregation on non-soluble forms of mutant Httex1.…”

Towards a comprehensive understanding of the contributions of mitochondrial dysfunction and oxidative stress in the pathogenesis and pathophysiology of Huntington's disease

“…mHTT has been shown to promote OS in neuronal and non‐neuronal cells (Hands, Sajjad, Newton, & Wyttenbach, ; Wyttenbach et al, ), which contributes to HD pathogenesis (Maiuri et al, ). Nuclear accumulation of mHTT is a key feature of HD and evidence suggests that OS plays a critical role in the nuclear accumulation of mHTT in HD (Son et al, ). Increased OS and vulnerability of the striatum to mHTT toxicity are key features in HD brains (Tabrizi et al, ).…”