scholarly journals Bi-allelic variants in the ER quality control mannosidase gene EDEM3 cause a congenital disorder of glycosylation

2021 ◽  
Author(s):  
Daniel L. Polla ◽  
Andrew C. Edmondson ◽  
Sandrine Duvet ◽  
Michael E. March ◽  
Ana Berta Sousa ◽  
...  
Keyword(s):  
Quality Control ◽  
Congenital Disorder ◽  
Er Quality Control ◽  
Allelic Variants ◽  
Congenital Disorder Of Glycosylation

The role of the ubiquitin–proteasome system in ER quality control

2005 ◽  
Vol 41 (1) ◽  
pp. 99 ◽  
Author(s):  
Yihong Ye
Keyword(s):  
Quality Control ◽  
Ubiquitin Proteasome System ◽  
Er Quality Control ◽  
Ubiquitin Proteasome

Functional analysis of three splicing mutations identified in the PMM2 gene: Toward a new therapy for congenital disorder of glycosylation type Ia

2009 ◽  
Vol 30 (5) ◽  
pp. 795-803 ◽  
Author(s):  
Ana I. Vega ◽  
Celia Pérez-Cerdá ◽  
Lourdes R. Desviat ◽  
Gert Matthijs ◽  
Magdalena Ugarte ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Congenital Disorder ◽  
Congenital Disorder Of Glycosylation ◽  
New Therapy ◽  
Splicing Mutations ◽  
Type Ia

Skeletal Dysplasia and Myelopathy in Congenital Disorder of Glycosylation Type IA

2006 ◽  
Vol 148 (1) ◽  
pp. 115-117 ◽  
Author(s):  
Steven M. Schade van Westrum ◽  
Paul J. Nederkoorn ◽  
P. Richard Schuurman ◽  
Tom Vulsma ◽  
Marinus Duran ◽  
...  
Keyword(s):  
Skeletal Dysplasia ◽  
Congenital Disorder ◽  
Congenital Disorder Of Glycosylation ◽  
Type Ia

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.

Screening for mutants defective in secretory protein maturation and ER quality control

Methods ◽  
2005 ◽  
Vol 35 (4) ◽  
pp. 366-372 ◽  
Author(s):  
Davis T.W. Ng
Keyword(s):  
Quality Control ◽  
Secretory Protein ◽  
Protein Maturation ◽  
Er Quality Control

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 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.

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