TY - JOUR
T1 - IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux
AU - Lee, Huikyong
AU - Noh, Jee Yeon
AU - Oh, Yumin
AU - Kim, Youngdoo
AU - Chang, Jae Woong
AU - Chung, Chul Woong
AU - Lee, Soon Tae
AU - Kim, Manho
AU - Ryu, Hoon
AU - Jung, Yong Keun
N1 - Funding Information:
This work was supported by the grants of Global Research Laboratory program (K21004000002-11A0500-00210), the Brain Research Center (2011K000279) and the Ubiquitome project (20110002137) to Y.-K.J. from the Korea Research Foundation funded by the Korean Government and the Korea Research Foundation Grant (KRF-2006-511-C00078) to H.L. H.L. and Y.O. were partly supported by the Brain Korea21 program.
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddr445
DO - 10.1093/hmg/ddr445
M3 - Article
C2 - 21954231
AN - SCOPUS:83455169115
SN - 0964-6906
VL - 21
SP - 101
EP - 114
JO - Human molecular genetics
JF - Human molecular genetics
IS - 1
M1 - ddr445
ER -