Abstract
Chronic stress in the endoplasmic reticulum (ER) underlies many degenerative and metabolic diseases involving apoptosis of vital cells. A well-established example is autosomal dominant retinitis pigmentosa (ADRP), an age-related retinal degenerative disease caused by mutant rhodopsins1,2. Similar mutant alleles of Drosophila Rhodopsin-1 also impose stress on the ER and cause age-related retinal degeneration in that organism3. Well-characterized signalling responses to ER stress, referred to as the unfolded protein response4 (UPR), induce various ER quality control genes that can suppress such retinal degeneration5. However, how cells activate cell death programs after chronic ER stress remains poorly understood. Here, we report the identification of a signalling pathway mediated by cdk5 and mekk1 required for ER-stress-induced apoptosis. Inactivation of these genes specifically suppressed apoptosis, without affecting other protective branches of the UPR. CDK5 phosphorylates MEKK1, and together, they activate the JNK pathway for apoptosis. Moreover, disruption of this pathway can delay the course of age-related retinal degeneration in a Drosophila model of ADRP. These findings establish a previously unrecognized branch of ER-stress response signalling involved in degenerative diseases.
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Acknowledgements
We thank E. Giniger (NIH, USA), K. Matsumoto (Nagoya University, Japan), M. Miura (Tokyo University, Japan), the VDRC and Bloomington stock centres for reagents, E. Robbins, M. Pagano and E. Zito for technical advice, and D. Ron for discussions and critical comments on the manuscript. This work was supported by the National Institutes of Health grant R01EY020866. H.D.R. is an Ellison Medical Foundation New Scholar.
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M-J.K. and H.D.R. designed the experiments. J.C. carried out the EPgy2 screen. All other experiments were carried out by M-J.K. H.D.R. wrote the paper and all authors read and edited the manuscript.
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Kang, MJ., Chung, J. & Ryoo, H. CDK5 and MEKK1 mediate pro-apoptotic signalling following endoplasmic reticulum stress in an autosomal dominant retinitis pigmentosa model. Nat Cell Biol 14, 409–415 (2012). https://doi.org/10.1038/ncb2447
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DOI: https://doi.org/10.1038/ncb2447
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