IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux

Lee, Huikyong; Noh, Jee-Yeon; Oh, Yumin; Kim, Youngdoo; Chang, Jae-Woong; Chung, Chul-Woong; Lee, Soon-Tae; Kim, Manho; Ryu, Hoon; Jung, Yong-Keun

doi:10.1093/hmg/ddr445

Cited by 157Genetic Neurodegenerative DiseasesEndoplasmic Reticulum Stress and DiseaseAutophagy in Disease and Therapy

IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux

Lee, Huikyong, Noh, Jee-Yeon, Oh, Yumin, Kim, Youngdoo, Chang, Jae-Woong, Chung, Chul-Woong, Lee, Soon-Tae, Kim, Manho +2 more·2012·Human Molecular Genetics

DOI 10.1093/hmg/ddr445

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Abstract

Huntington's disease (HD), an inherited neurodegenerative disorder, is caused by an expansion of cytosine-adenine-guanine repeats in the huntingtin gene. The aggregation of mutant huntingtin (mtHTT) and striatal cell loss are representative features to cause uncontrolled movement and cognitive defect in HD. However, underlying mechanism of mtHTT aggregation and cell toxicity remains still elusive. Here, to find new genes modulating mtHTT aggregation, we performed cell-based functional screening using the cDNA expression library and isolated IRE1 gene, one of endoplasmic reticulum (ER) stress sensors. Ectopic expression of IRE1 led to its self-activation and accumulated detergent-resistant mtHTT aggregates. Treatment of neuronal cells with ER stress insults, tunicamycin and thapsigargin, increased mtHTT aggregation via IRE1 activation. The kinase activity of IRE1, but not the endoribonuclease activity, was necessary to stimulate mtHTT aggregation and increased death of neuronal cells, including SH-SY5Y and STHdhQ111/111 huntingtin knock-in striatal cells. Interestingly, ER stress impaired autophagy flux via IRE1-TRAF2 pathway, thus enhancing cellular accumulation of mtHTT. Atg5 deficiency in M5-7 cells increased mtHTT aggregation but blocked ER stress-induced mtHTT aggregation. Further, ER stress markers including p-IRE1 and autophagy markers such as p62 were up-regulated exclusively in the striatal tissues of HD mouse models and in HD patients. Moreover, down-regulation of IRE1 expression rescues the rough-eye phenotype by mtHTT in a HD fly model. These results suggest that IRE1 plays an essential role in ER stress-mediated aggregation of mtHTT via the inhibition of autophagy flux and thus neuronal toxicity of mtHTT aggregates in HD.

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Protein clearance by ubiquitin and autophagy is severely impaired in Huntington's disease, shown by accumulated ubiquitinated species in patient and mouse brain and increased p62.
“Ubiquitinand autophagy-based protein clearance systems are highly impaired in Huntington's disease, as evidenced by a striking build-up of ubiquitinated species in patient brain and mouse models”
From Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease (2020) · cites this paper as Lee et al., 2012
Expression of mutant HTT drives a maladaptive unfolded protein response, which leads to ERN1/IRE1-dependent inhibition of autophagy.
“(v) drives a maladaptive unfolded protein response, which leads to ERN1/IRE1 (endoplasmic reticulum to nucleus signaling 1)‐dependent inhibition of autophagy (Lee et al, 2012);”
From Autophagy in major human diseases (2021) · cites this paper as Lee et al, 2012

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Huntingtin is required for neurogenesis and is not impaired by the Huntington's disease CAG expansion
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Authors: Lee, H., Noh, J.-Y., Oh, Y., Kim, Y., Chang, J.-W., Chung, C.-W., Lee, S.-T., Kim, M., Ryu, H., & Jung, Y.-K.
Affiliations: Seoul National University (KR)
LG (South Korea) (KR)
Boston University (US)
Corresponding author: Jung, Yong-Keun
ORCID: Chung, Chul-Woong
Lee, Soon-Tae
Kim, Manho
Ryu, Hoon
Jung, Yong-Keun
Venue: Human Molecular Genetics
Publisher: Oxford University Press (OUP)
Published: 2011-09-27
Volume: 21
Issue: 1
Pages: 101-114
ISSN: 0964-6906 (ISSN-L)
1460-2083
DOI: 10.1093/hmg/ddr445
OpenAlex: W2137288609
Cited by: 157
References: 46
Citations by year: 2026: 3 · 2025: 6 · 2024: 7 · 2023: 15 · 2022: 14 · 2021: 16 · 2020: 12 · 2019: 13 · 2018: 12 · 2017: 10 · 2016: 9 · 2015: 11 · 2014: 15 · 2013: 8 · 2012: 6
FWCI: 3.83
Type: journal article
Language: en
Open access: closed
Locations: Human Molecular Genetics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords: IRE1, Huntington's disease, mutant huntingtin aggregation, endoplasmic reticulum stress, autophagic flux, neurotoxicity, ATG5, p62, striatal cells, rough eye phenotype, tunicamycin, thapsigargin, neurodegeneration
MeSH terms: Huntingtin Protein, Animals, Autophagy, Cell Line, Cells, Cultured, Endoplasmic Reticulum, Endoribonucleases, Humans, Huntington Disease, Membrane Proteins, Mutation, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Down-Regulation, Protein Serine-Threonine Kinases, Mice, Rats, Endoplasmic Reticulum Stress

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IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux

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