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 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.
Department of Genetics, University of Seville, 41012 Seville, Spain.
Natalia
0000-0003-3333-697X
N
Sikorska
Department of Genetics, University of Seville, 41012 Seville, Spain.
Leticia
L
Lemus
National Centre of Competence in Research, Chemical Biology, Sciences II, University of Geneva, 1211 Geneva 4, Switzerland Department of Biochemistry, Sciences II, University of Geneva, 1211 Geneva 4, Switzerland.
Auxiliadora
A
Aguilera-Romero
Department of Cell Biology, University of Seville, 41012 Seville, Spain Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, 41013 Seville, Spain.
Javier
0000-0002-7149-1690
J
Manzano-Lopez
National Centre of Competence in Research, Chemical Biology, Sciences II, University of Geneva, 1211 Geneva 4, Switzerland Department of Biochemistry, Sciences II, University of Geneva, 1211 Geneva 4, Switzerland.
Howard
0000-0003-4680-9422
H
Riezman
Department of Cell Biology, University of Seville, 41012 Seville, Spain Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío, Consejo Superior de Investigaciones Científicas, University of Seville, 41013 Seville, Spain.
Manuel
0000-0001-8011-6991
M
Muñiz
Department of Genetics, University of Seville, 41012 Seville, Spain vgoder@us.es.
Veit
0000-0003-0854-4873
V
Goder
D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000502:physiology*; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D005656:Fungal Proteins / Q000378:metabolism*; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding; D015003:Yeasts / Q000378:metabolism / Q000502:physiology
D005656:Fungal Proteins; D017261:Glycosylphosphatidylinositols; C081751:plasmanylinositol glycan