scholarly journals Proteasome and thiol involvement in quality control of glycosylphosphatidylinositol anchor addition

1998 ◽  
Vol 332 (1) ◽  
pp. 111-118 ◽  
Author(s):  
Barry WILBOURN ◽  
Darren N. NESBETH ◽  
Linda J. WAINWRIGHT ◽  
Mark C. FIELD
Keyword(s):  
Quality Control ◽  
Cysteine Residue ◽  
Retention Mechanism ◽  
Secretory Proteins ◽  
Aggregate Formation ◽  
Er Quality Control ◽  
Additional Information ◽  
Intracellular Degradation ◽  
Processing Signal ◽  
Ubiquitination System

Improperly processed secretory proteins are degraded by a hydrolytic system that is associated with the endoplasmic reticulum (ER) and appears to involve re-export of lumenal proteins into the cytoplasm for ultimate degradation by the proteasome. The chimaeric protein hGHDAF28, which contains a crippled glycosylphosphatidylinositol (GPI) C-terminal signal peptide, is degraded by a pathway highly similar to that for other ER-retained proteins and is characterized by formation of disulphide-linked aggregates, failure to reach the Golgi complex and intracellular degradation with a half life of ∼ 2 h. Here we show that N-acetyl-leucinal-leucinal-norleucinal, MG-132 and lactacystin, all inhibitors of the proteasome, protect hGHDAF28; hGHDAF28 is still proteolytically cleaved in the presence of lactacystin or MG-132, by the removal of ∼ 2 kDa, but the truncated fragment is not processed further. We demonstrate that the ubiquitination system accelerates ER-degradation of hGHDAF28, but is not essential to the process. Overall, these findings indicate that GPI quality control is mediated by the cytoplasmic proteasome. We also show that the presence of a cysteine residue in the GPI signal of hGHDAF28 is required for retention and degradation, as mutation of this residue to serine results in secretion of the fusion protein, implicating thiol-mediated retention as a mechanism for quality control of some GPI signals. Removal of the cysteine also prevents inclusion of hGHDAF28 in disulphide-linked aggregates, indicating that aggregate formation is an additional retention mechanism for this class of protein. Therefore our data suggest that an unpaired terminal cysteine is the retention motif of the hGHDAF28 GPI-processing signal and that additional information may be required for efficient engagement of ER quality control systems by the majority of GPI signals which lack cysteine residues.

scholarly journals Chaperone-Mediated Reflux of Secretory Proteins to the Cytosol During Endoplasmic Reticulum Stress

2019 ◽  
Author(s):  
Aeid Igbaria ◽  
Philip I. Merksamer ◽  
Ala Trusina ◽  
Firehiwot Tilahun ◽  
Jefferey R. Johnson ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Fluorescent Protein ◽  
Control Process ◽  
Secretory Proteins ◽  
Er Quality Control ◽  
Quality Control Process

ABSTRACTDiverse perturbations to endoplasmic reticulum (ER) functions compromise the proper folding and structural maturation of secretory proteins. To study secretory pathway physiology during such “ER stress”, we employed an ER-targeted, redox-responsive, green fluorescent protein—eroGFP—that reports on ambient changes in oxidizing potential. Here we find that diverse ER stress agents cause properly folded, ER-resident eroGFP (and other ER luminal proteins) to “reflux” back to the reducing environment of the cytosol as intact, folded proteins. By utilizing eroGFP in a comprehensive genetic screen in S. cerevisiae, we show that ER protein reflux during ER stress requires specific chaperones and co-chaperones residing in both the ER and the cytosol. Chaperone-mediated ER protein reflux does not require E3 ligase activity, and proceeds even more vigorously when these ER-associated degradation (ERAD) factors are crippled, suggesting that reflux may work in parallel with ERAD. In summary, chaperone-mediated ER-protein reflux may be a conserved protein quality control process that evolved to maintain secretory pathway homeostasis during ER protein-folding stress.SIGNIFICANCEApproximately one third of eukaryotic proteins are synthesized on ribosomes attached to the endoplasmic reticulum (ER) membrane. Many of these polypeptides co- or post-translationally translocate into the ER, wherein they fold and mature. An ER quality-control system proofreads these proteins by facilitating their folding and modification, while eliminating misfolded proteins through ER-associated degradation (ERAD). Yet, the fate of many secretory proteins during ER stress is not completely understood. Here, we uncovered an ER-stress induced “protein reflux” system that delivers intact, folded ER luminal proteins back to the cytosol without degrading them. We found that ER protein reflux works in parallel to ERAD and requires distinct ER-resident and cytosolic chaperones and co-chaperones.

ERp57 and PDI: multifunctional protein disulfide isomerases with similar domain architectures but differing substrate–partner associationsThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB — Membrane Proteins in Health and Disease.

2006 ◽  
Vol 84 (6) ◽  
pp. 881-889 ◽  
Author(s):  
P. Maattanen ◽  
G. Kozlov ◽  
K. Gehring ◽  
D.Y. Thomas
Keyword(s):  
Quality Control ◽  
Disulfide Bonds ◽  
Secretory Proteins ◽  
Er Quality Control ◽  
Multifunctional Protein ◽  
Health And Disease ◽  
Disulfide Isomerases ◽  
Protein Disulfide ◽  
Selection Of ◽  
Similar Domain

Secretory proteins become folded and acquire stabilizing disulfide bonds in the endoplasmic reticulum (ER). Correct disulfide bond formation is a key step in ER quality control (ERQC). Proteins with incorrect disulfide bonds are recognized by the quality control machinery and are retrotranslocated into the cytosol where they are degraded by the proteasome. The mammalian ER contains 17 disulfide isomerases and at least one of them, ERp57, works in conjunction with the ER lectin-like chaperones calnexin and calreticulin. The targeting of ERp57 to calnexin–calreticulin is mediated by its noncatalytic b′ domain, and analogous domains in other disulfide isomerases likely determine their substrate and partner preferences. This review discusses some explanations for the multiplicity of disulfide isomerases and highlights structural differences in the b′ domains of PDI and ERp57 as an example of how noncatalytic domains define specialized roles in oxidative folding.

scholarly journals Single, context-specific glycans can target misfolded glycoproteins for ER-associated degradation

2005 ◽  
Vol 169 (1) ◽  
pp. 73-82 ◽  
Author(s):  
Eric D. Spear ◽  
Davis T.W. Ng
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Secretory Protein ◽  
Carboxypeptidase Y ◽  
Er Quality Control ◽  
Systematic Analysis ◽  
Proteinase A ◽  
Context Specific ◽  
The Relationship ◽  
Erad Pathway

The endoplasmic reticulum (ER) maintains an environment essential for secretory protein folding. Consequently, the premature transport of polypeptides would be harmful to the cell. To avert this scenario, mechanisms collectively termed “ER quality control” prevent the transport of nascent polypeptides until they properly fold. Irreversibly misfolded molecules are sorted for disposal by the ER-associated degradation (ERAD) pathway. To better understand the relationship between quality control and ERAD, we studied a new misfolded variant of carboxypeptidase Y (CPY). The molecule was recognized and retained by ER quality control but failed to enter the ERAD pathway. Systematic analysis revealed that a single, specific N-linked glycan of CPY was required for sorting into the pathway. The determinant is dependent on the putative lectin-like receptor Htm1/Mnl1p. The discovery of a similar signal in misfolded proteinase A supported the generality of the mechanism. These studies show that specific signals embedded in glycoproteins can direct their degradation if they fail to fold.

scholarly journals Limited ER quality control for GPI-anchored proteins

2016 ◽  
Vol 213 (6) ◽  
pp. 693-704 ◽  
Author(s):  
Natalia Sikorska ◽  
Leticia Lemus ◽  
Auxiliadora Aguilera-Romero ◽  
Javier Manzano-Lopez ◽  
Howard Riezman ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Misfolded Proteins ◽  
Control Mechanisms ◽  
Gpi Anchor ◽  
Er Quality Control ◽  
Entire Class ◽  
Er Export ◽  
Export Signal

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.

scholarly journals UDP-GlC:glycoprotein glucosyltransferase-glucosidase II, the ying-yang of the ER quality control

2010 ◽  
Vol 21 (5) ◽  
pp. 491-499 ◽  
Author(s):  
Cecilia D’Alessio ◽  
Julio J. Caramelo ◽  
Armando J. Parodi
Keyword(s):  
Quality Control ◽  
Er Quality Control ◽  
Glucosidase Ii

scholarly journals Mutation-specific peripheral and ER quality control of hERG channel cell-surface expression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Brian Foo ◽  
Camille Barbier ◽  
Kevin Guo ◽  
Jaminie Vasantharuban ◽  
Gergely L. Lukacs ◽  
...  
Keyword(s):  
Quality Control ◽  
Cell Surface ◽  
Surface Expression ◽  
Herg Channel ◽  
Cell Surface Expression ◽  
Er Quality Control
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