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EMBO J., advance online publication 14 December 2006
Unfolded protein response in a Drosophila model for retinal degeneration
Abstract
Hyung Don Ryoo1, 2, 3, Pedro M Domingos2, 3, Min-Ji Kang1 and Hermann Steller2
1 Department of Cell Biology, NYU School of Medicine, New York, NY, USA
2 Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA
To whom correspondence should be addressed
Hermann Steller, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA. Tel.: +1 212 327 7075; Fax: +1 212 327 7076
3 These authors contributed equally to this work
Abstract
Stress in the endoplasmic reticulum (ER stress) and its cellular response, the unfolded protein response (UPR), are implicated in a wide variety of diseases, but its significance in many disorders remains to be validated in vivo. Here, we analyzed a branch of the UPR mediated by xbp1 in Drosophila to establish its role in neurodegenerative diseases. The Drosophila xbp1 mRNA undergoes ire-1-mediated unconventional splicing in response to ER stress, and this property was used to develop a specific UPR marker, xbp1-EGFP, in which EGFP is expressed in frame only after ER stress. xbp1-EGFP responds specifically to ER stress, but not to proteins that form cytoplasmic aggregates. The ire-1/xbp1 pathway regulates heat shock cognate protein 3 (hsc3), an ER chaperone. xbp1 splicing and hsc3 induction occur in the retina of ninaEG69D-/+, a Drosophila model for autosomal dominant retinitis pigmentosa (ADRP), and reduction of xbp1 gene dosage accelerates retinal degeneration of these animals. These results demonstrate the role of the UPR in the Drosophila ADRP model and open new opportunities for examining the UPR in other Drosophila disease models.
1 Department of Cell Biology, NYU School of Medicine, New York, NY, USA
2 Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA
To whom correspondence should be addressed
Hermann Steller, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA. Tel.: +1 212 327 7075; Fax: +1 212 327 7076
3 These authors contributed equally to this work
Abstract
Stress in the endoplasmic reticulum (ER stress) and its cellular response, the unfolded protein response (UPR), are implicated in a wide variety of diseases, but its significance in many disorders remains to be validated in vivo. Here, we analyzed a branch of the UPR mediated by xbp1 in Drosophila to establish its role in neurodegenerative diseases. The Drosophila xbp1 mRNA undergoes ire-1-mediated unconventional splicing in response to ER stress, and this property was used to develop a specific UPR marker, xbp1-EGFP, in which EGFP is expressed in frame only after ER stress. xbp1-EGFP responds specifically to ER stress, but not to proteins that form cytoplasmic aggregates. The ire-1/xbp1 pathway regulates heat shock cognate protein 3 (hsc3), an ER chaperone. xbp1 splicing and hsc3 induction occur in the retina of ninaEG69D-/+, a Drosophila model for autosomal dominant retinitis pigmentosa (ADRP), and reduction of xbp1 gene dosage accelerates retinal degeneration of these animals. These results demonstrate the role of the UPR in the Drosophila ADRP model and open new opportunities for examining the UPR in other Drosophila disease models.
논문정보
- Research article
- 2006년 12월 (BRIC 등록일 )
- 국외 연구진
- 의약학 > 분자세포의학
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