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IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin

Endoplasmic reticulum (ER) is responsible for folding of secreted and membrane proteins in eukaryotic cells. Disruption of ER protein folding leads to ER stress. Chronic ER stress can cause cell death and is proposed to underlie the pathogenesis of many human diseases. Inositol-requiring enzyme 1 (I...

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Autores principales: Chiang, Wei-Chieh, Messah, Carissa, Lin, Jonathan H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290636/
https://www.ncbi.nlm.nih.gov/pubmed/22219383
http://dx.doi.org/10.1091/mbc.E11-08-0663
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author Chiang, Wei-Chieh
Messah, Carissa
Lin, Jonathan H.
author_facet Chiang, Wei-Chieh
Messah, Carissa
Lin, Jonathan H.
author_sort Chiang, Wei-Chieh
collection PubMed
description Endoplasmic reticulum (ER) is responsible for folding of secreted and membrane proteins in eukaryotic cells. Disruption of ER protein folding leads to ER stress. Chronic ER stress can cause cell death and is proposed to underlie the pathogenesis of many human diseases. Inositol-requiring enzyme 1 (IRE1) directs a key unfolded protein response signaling pathway that controls the fidelity of ER protein folding. IRE1 signaling may be particularly helpful in preventing chronic ER stress and cell injury by alleviating protein misfolding in the ER. To examine this, we used a chemical-genetic approach to selectively activate IRE1 in mammalian cells and tested how artificial IRE1 signaling affected the fate of misfolded P23H rhodopsin linked to photoreceptor cell death. We found that IRE1 signaling robustly promoted the degradation of misfolded P23H rhodopsin without affecting its wild-type counterpart. We also found that IRE1 used both proteasomal and lysosomal degradation pathways to remove P23H rhodopsin. Surprisingly, when one degradation pathway was compromised, IRE1 signaling could still promote misfolded rhodopsin degradation using the remaining pathway. Last, we showed that IRE1 signaling also reduced levels of several other misfolded rhodopsins with lesser effects on misfolded cystic fibrosis transmembrane conductance regulator. Our findings reveal the diversity of proteolytic mechanisms used by IRE1 to eliminate misfolded rhodopsin.
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spelling pubmed-32906362012-05-16 IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin Chiang, Wei-Chieh Messah, Carissa Lin, Jonathan H. Mol Biol Cell Articles Endoplasmic reticulum (ER) is responsible for folding of secreted and membrane proteins in eukaryotic cells. Disruption of ER protein folding leads to ER stress. Chronic ER stress can cause cell death and is proposed to underlie the pathogenesis of many human diseases. Inositol-requiring enzyme 1 (IRE1) directs a key unfolded protein response signaling pathway that controls the fidelity of ER protein folding. IRE1 signaling may be particularly helpful in preventing chronic ER stress and cell injury by alleviating protein misfolding in the ER. To examine this, we used a chemical-genetic approach to selectively activate IRE1 in mammalian cells and tested how artificial IRE1 signaling affected the fate of misfolded P23H rhodopsin linked to photoreceptor cell death. We found that IRE1 signaling robustly promoted the degradation of misfolded P23H rhodopsin without affecting its wild-type counterpart. We also found that IRE1 used both proteasomal and lysosomal degradation pathways to remove P23H rhodopsin. Surprisingly, when one degradation pathway was compromised, IRE1 signaling could still promote misfolded rhodopsin degradation using the remaining pathway. Last, we showed that IRE1 signaling also reduced levels of several other misfolded rhodopsins with lesser effects on misfolded cystic fibrosis transmembrane conductance regulator. Our findings reveal the diversity of proteolytic mechanisms used by IRE1 to eliminate misfolded rhodopsin. The American Society for Cell Biology 2012-03-01 /pmc/articles/PMC3290636/ /pubmed/22219383 http://dx.doi.org/10.1091/mbc.E11-08-0663 Text en © 2012 Chiang et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology.
spellingShingle Articles
Chiang, Wei-Chieh
Messah, Carissa
Lin, Jonathan H.
IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin
title IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin
title_full IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin
title_fullStr IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin
title_full_unstemmed IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin
title_short IRE1 directs proteasomal and lysosomal degradation of misfolded rhodopsin
title_sort ire1 directs proteasomal and lysosomal degradation of misfolded rhodopsin
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3290636/
https://www.ncbi.nlm.nih.gov/pubmed/22219383
http://dx.doi.org/10.1091/mbc.E11-08-0663
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