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Robust Endoplasmic Reticulum-Associated Degradation of Rhodopsin Precedes Retinal Degeneration

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Abstract

Rhodopsin is a G protein-coupled receptor essential for vision and rod photoreceptor viability. Disease-associated rhodopsin mutations, such as P23H rhodopsin, cause rhodopsin protein misfolding and trigger endoplasmic reticulum (ER) stress, activating the unfolded protein response (UPR). The pathophysiologic effects of ER stress and UPR activation on photoreceptors are unclear. Here, by examining P23H rhodopsin knock-in mice, we found that the UPR inositol-requiring enzyme 1 (IRE1) signaling pathway is strongly activated in misfolded rhodopsin-expressing photoreceptors. IRE1 significantly upregulated ER-associated protein degradation (ERAD), triggering pronounced P23H rhodopsin degradation. Rhodopsin protein loss occurred as soon as photoreceptors developed, preceding photoreceptor cell death. By contrast, IRE1 activation did not affect JNK signaling or rhodopsin mRNA levels. Interestingly, pro-apoptotic signaling from the PERK UPR pathway was also not induced. Our findings reveal that an early and significant pathophysiologic effect of ER stress in photoreceptors is the highly efficient elimination of misfolded rhodopsin protein. We propose that early disruption of rhodopsin protein homeostasis in photoreceptors could contribute to retinal degeneration.

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Abbreviations

ERAD:

ER-associated protein degradation

IRE1:

Inositol-requiring enzyme 1

ONL:

Outer nuclear layer

PERK:

PKR-like endoplasmic reticulum kinase

qPCR:

Quantitative real-time PCR

RP:

Retinitis pigmentosa

RIS:

Rod inner segment

ROS:

Rod outer segment

UPR:

Unfolded protein response

XBP-1:

X-box-binding protein 1

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Acknowledgements

We thank J. Han, N. Hiramatsu, C. Sigurdson, W. C. Smith, S. Tsang, and L. Wiseman for helpful suggestions and reagents. These studies were supported by NIH grants EY001919, P30EY002162, and EY020846, Foundation Fighting Blindness, UCSD Neuroscience Microscopy Shared Facility P30 NS047101, and VA Merit award BX002284. W.-C. Chiang received postdoctoral support from the Fight-for-Sight Foundation.

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The authors declare no conflict of interest.

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Chiang, WC., Kroeger, H., Sakami, S. et al. Robust Endoplasmic Reticulum-Associated Degradation of Rhodopsin Precedes Retinal Degeneration. Mol Neurobiol 52, 679–695 (2015). https://doi.org/10.1007/s12035-014-8881-8

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