October 2012
Volume 53, Issue 11
Research Highlight  |   October 2012
Unpicking the UPR
Investigative Ophthalmology & Visual Science October 2012, Vol.53, 7167. doi:https://doi.org/10.1167/iovs.12-11004
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      Michael E. Cheetham; Unpicking the UPR. Invest. Ophthalmol. Vis. Sci. 2012;53(11):7167. doi: https://doi.org/10.1167/iovs.12-11004.

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      © ARVO (1962-2015); The Authors (2016-present)

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Mutationsin rhodopsin that lead to protein misfolding are a major cause of retinitis pigmentosa (RP). 1 Cells respond to misfolded proteins in their endoplasmic reticulum (ER) by inducing a transcriptional program known as the “unfolded protein response” (UPR), and the UPR is induced in models of rhodopsin RP. 2 The UPR has three branches that sense protein misfolding and initiate this adaptive response: the RNase inositol-requiring protein 1 (IRE1), which is activated to splice XBP-1 mRNA to produce a transcription factor; the activating transcription factor 6 (ATF6), which is released from the ER by proteolytic cleavage to stimulate transcription; and the protein kinase RNA-like ER kinase (PERK), which phosphorylates eukaryotic translation initiator factor 2α (eIF2α) and stimulates the translation of activating transcription factor 4 (ATF4). This complexity has made it difficult to determine the relative contribution of each branch of the UPR to the stress response and the degradation of specific proteins. In this issue of IOVS, Chiang et al. 3 report the specific chemical genetic manipulation of the ATF6 or PERK pathways in cell culture and investigate their effect on rhodopsin expression. When these data are combined with the recent investigation of IRE1 activation by a similar approach, 4 it becomes clearer which branches of the UPR might be critical for dealing with mutant rhodopsin. In particular, activation of IRE1 or ATF6 enhanced the degradation of mutant rhodopsin, whereas PERK activation caused a non-specific reduction in control and mutant rhodopsin translation. Therefore, the direct activation of IRE1 or ATF6 and their downstream targets (such as BiP, EDEM1, and VCP) 57 potentially could be used to target mutant rhodopsin therapeutically. Furthermore, there is growing evidence for UPR induction in several forms of retinal degeneration and understanding how its different branches affect retinal biology, as well as their potential manipulation, could be important for a wide range of retinal diseases. 
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Athanasiou D Kosmaoglou M Kanuga N BiP prevents rod opsin aggregation. Mol Biol Cell . 2012;23:3522–3531. [CrossRef] [PubMed]
Kosmaoglou M Kanuga N Aguila M Garriga P Cheetham ME. A dual role for EDEM1 in the processing of rod opsin. J Cell Sci . 2009;122:4465–4472. [CrossRef] [PubMed]
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