Robust Endoplasmic Reticulum-Associated Degradation of Rhodopsin Precedes Retinal Degeneration

Mol Neurobiol. 2015 Aug;52(1):679-95. doi: 10.1007/s12035-014-8881-8. Epub 2014 Oct 2.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis
  • Endoplasmic Reticulum Stress
  • Endoplasmic Reticulum-Associated Degradation*
  • Gene Knock-In Techniques
  • Immunoprecipitation
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Protein Serine-Threonine Kinases / metabolism
  • Proteolysis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Retina / metabolism
  • Retina / pathology
  • Retina / ultrastructure
  • Retinal Degeneration / metabolism*
  • Retinal Degeneration / pathology*
  • Retinal Photoreceptor Cell Inner Segment / metabolism
  • Retinal Photoreceptor Cell Inner Segment / pathology
  • Retinal Photoreceptor Cell Inner Segment / ultrastructure
  • Rhodopsin / genetics
  • Rhodopsin / metabolism*
  • Signal Transduction
  • Transcription Factor CHOP / metabolism
  • Ubiquitination


  • Membrane Proteins
  • RNA, Messenger
  • Transcription Factor CHOP
  • Rhodopsin
  • Ern2 protein, mouse
  • Protein Serine-Threonine Kinases