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

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

Research output: Contribution to journalArticle

Abstract

Huntington's disease (HD), an inherited neurodegenerative disorder, is caused by an expansion of cytosineadenine-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.

Original languageEnglish (US)
Article numberddr445
Pages (from-to)101-114
Number of pages14
JournalHuman molecular genetics
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    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. (2012). IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux. Human molecular genetics, 21(1), 101-114. [ddr445]. https://doi.org/10.1093/hmg/ddr445