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ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in Drosophila and mice

Defective rhodopsin homeostasis is one of the major causes of retinal degeneration, including the disease Retinitis pigmentosa. To identify cellular factors required for the biosynthesis of rhodopsin, we performed a genome-wide genetic screen in Drosophila for mutants with reduced levels of rhodopsi...

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Autores principales: Xiong, Liangyao, Zhang, Lin, Yang, Yeming, Li, Na, Lai, Wenjia, Wang, Fengchao, Zhu, Xianjun, Wang, Tao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206144/
https://www.ncbi.nlm.nih.gov/pubmed/31263175
http://dx.doi.org/10.1038/s41418-019-0378-6
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author Xiong, Liangyao
Zhang, Lin
Yang, Yeming
Li, Na
Lai, Wenjia
Wang, Fengchao
Zhu, Xianjun
Wang, Tao
author_facet Xiong, Liangyao
Zhang, Lin
Yang, Yeming
Li, Na
Lai, Wenjia
Wang, Fengchao
Zhu, Xianjun
Wang, Tao
author_sort Xiong, Liangyao
collection PubMed
description Defective rhodopsin homeostasis is one of the major causes of retinal degeneration, including the disease Retinitis pigmentosa. To identify cellular factors required for the biosynthesis of rhodopsin, we performed a genome-wide genetic screen in Drosophila for mutants with reduced levels of rhodopsin. We isolated loss-of-function alleles in endoplasmic reticulum membrane protein complex 3 (emc3), emc5, and emc6, each of which exhibited defective phototransduction and photoreceptor cell degeneration. EMC3, EMC5, and EMC6 were essential for rhodopsin synthesis independent of the ER associated degradation (ERAD) pathway, which eliminates misfolded proteins. We generated null mutations for all EMC subunits, and further demonstrated that different EMC subunits play roles in different cellular functions. Conditional knockout of the Emc3 gene in mice led to mislocalization of rhodopsin protein and death of cone and rod photoreceptor cells. These data indicate conserved roles for EMC subunits in maintaining rhodopsin homeostasis and photoreceptor function, and suggest that retinal degeneration may also be caused by defects in early biosynthesis of rhodopsin.
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spelling pubmed-72061442020-05-08 ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in Drosophila and mice Xiong, Liangyao Zhang, Lin Yang, Yeming Li, Na Lai, Wenjia Wang, Fengchao Zhu, Xianjun Wang, Tao Cell Death Differ Article Defective rhodopsin homeostasis is one of the major causes of retinal degeneration, including the disease Retinitis pigmentosa. To identify cellular factors required for the biosynthesis of rhodopsin, we performed a genome-wide genetic screen in Drosophila for mutants with reduced levels of rhodopsin. We isolated loss-of-function alleles in endoplasmic reticulum membrane protein complex 3 (emc3), emc5, and emc6, each of which exhibited defective phototransduction and photoreceptor cell degeneration. EMC3, EMC5, and EMC6 were essential for rhodopsin synthesis independent of the ER associated degradation (ERAD) pathway, which eliminates misfolded proteins. We generated null mutations for all EMC subunits, and further demonstrated that different EMC subunits play roles in different cellular functions. Conditional knockout of the Emc3 gene in mice led to mislocalization of rhodopsin protein and death of cone and rod photoreceptor cells. These data indicate conserved roles for EMC subunits in maintaining rhodopsin homeostasis and photoreceptor function, and suggest that retinal degeneration may also be caused by defects in early biosynthesis of rhodopsin. Nature Publishing Group UK 2019-07-01 2020-02 /pmc/articles/PMC7206144/ /pubmed/31263175 http://dx.doi.org/10.1038/s41418-019-0378-6 Text en © The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Xiong, Liangyao
Zhang, Lin
Yang, Yeming
Li, Na
Lai, Wenjia
Wang, Fengchao
Zhu, Xianjun
Wang, Tao
ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in Drosophila and mice
title ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in Drosophila and mice
title_full ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in Drosophila and mice
title_fullStr ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in Drosophila and mice
title_full_unstemmed ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in Drosophila and mice
title_short ER complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in Drosophila and mice
title_sort er complex proteins are required for rhodopsin biosynthesis and photoreceptor survival in drosophila and mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206144/
https://www.ncbi.nlm.nih.gov/pubmed/31263175
http://dx.doi.org/10.1038/s41418-019-0378-6
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