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Limited ER quality control for GPI-anchored proteins

Endoplasmic reticulum (ER) quality control mechanisms target terminally misfolded proteins for ER-associated degradation (ERAD). Misfolded glycophosphatidylinositol-anchored proteins (GPI-APs) are, however, generally poor ERAD substrates and are targeted mainly to the vacuole/lysosome for degradatio...

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Autores principales: Sikorska, Natalia, Lemus, Leticia, Aguilera-Romero, Auxiliadora, Manzano-Lopez, Javier, Riezman, Howard, Muñiz, Manuel, Goder, Veit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915193/
https://www.ncbi.nlm.nih.gov/pubmed/27325793
http://dx.doi.org/10.1083/jcb.201602010
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author Sikorska, Natalia
Lemus, Leticia
Aguilera-Romero, Auxiliadora
Manzano-Lopez, Javier
Riezman, Howard
Muñiz, Manuel
Goder, Veit
author_facet Sikorska, Natalia
Lemus, Leticia
Aguilera-Romero, Auxiliadora
Manzano-Lopez, Javier
Riezman, Howard
Muñiz, Manuel
Goder, Veit
author_sort Sikorska, Natalia
collection PubMed
description Endoplasmic reticulum (ER) quality control mechanisms target terminally misfolded proteins for ER-associated degradation (ERAD). Misfolded glycophosphatidylinositol-anchored proteins (GPI-APs) are, however, generally poor ERAD substrates and are targeted mainly to the vacuole/lysosome for degradation, leading to predictions that a GPI anchor sterically obstructs ERAD. Here we analyzed the degradation of the misfolded GPI-AP Gas1* in yeast. We could efficiently route Gas1* to Hrd1-dependent ERAD and provide evidence that it contains a GPI anchor, ruling out that a GPI anchor obstructs ERAD. Instead, we show that the normally decreased susceptibility of Gas1* to ERAD is caused by canonical remodeling of its GPI anchor, which occurs in all GPI-APs and provides a protein-independent ER export signal. Thus, GPI anchor remodeling is independent of protein folding and leads to efficient ER export of even misfolded species. Our data imply that ER quality control is limited for the entire class of GPI-APs, many of them being clinically relevant.
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spelling pubmed-49151932016-12-20 Limited ER quality control for GPI-anchored proteins Sikorska, Natalia Lemus, Leticia Aguilera-Romero, Auxiliadora Manzano-Lopez, Javier Riezman, Howard Muñiz, Manuel Goder, Veit J Cell Biol Research Articles Endoplasmic reticulum (ER) quality control mechanisms target terminally misfolded proteins for ER-associated degradation (ERAD). Misfolded glycophosphatidylinositol-anchored proteins (GPI-APs) are, however, generally poor ERAD substrates and are targeted mainly to the vacuole/lysosome for degradation, leading to predictions that a GPI anchor sterically obstructs ERAD. Here we analyzed the degradation of the misfolded GPI-AP Gas1* in yeast. We could efficiently route Gas1* to Hrd1-dependent ERAD and provide evidence that it contains a GPI anchor, ruling out that a GPI anchor obstructs ERAD. Instead, we show that the normally decreased susceptibility of Gas1* to ERAD is caused by canonical remodeling of its GPI anchor, which occurs in all GPI-APs and provides a protein-independent ER export signal. Thus, GPI anchor remodeling is independent of protein folding and leads to efficient ER export of even misfolded species. Our data imply that ER quality control is limited for the entire class of GPI-APs, many of them being clinically relevant. The Rockefeller University Press 2016-06-20 /pmc/articles/PMC4915193/ /pubmed/27325793 http://dx.doi.org/10.1083/jcb.201602010 Text en © 2016 Sikorska et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).
spellingShingle Research Articles
Sikorska, Natalia
Lemus, Leticia
Aguilera-Romero, Auxiliadora
Manzano-Lopez, Javier
Riezman, Howard
Muñiz, Manuel
Goder, Veit
Limited ER quality control for GPI-anchored proteins
title Limited ER quality control for GPI-anchored proteins
title_full Limited ER quality control for GPI-anchored proteins
title_fullStr Limited ER quality control for GPI-anchored proteins
title_full_unstemmed Limited ER quality control for GPI-anchored proteins
title_short Limited ER quality control for GPI-anchored proteins
title_sort limited er quality control for gpi-anchored proteins
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915193/
https://www.ncbi.nlm.nih.gov/pubmed/27325793
http://dx.doi.org/10.1083/jcb.201602010
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