scholarly journals Recognition and ER Quality Control of Misfolded Formylglycine-Generating Enzyme by Protein Disulfide Isomerase

Cell Reports ◽  
2018 ◽  
Vol 24 (1) ◽  
pp. 27-37.e4 ◽  
Author(s):  
Lars Schlotawa ◽  
Michaela Wachs ◽  
Olaf Bernhard ◽  
Franz J. Mayer ◽  
Thomas Dierks ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Disulfide Isomerase ◽  
Er Quality Control ◽  
Disulfide Isomerase ◽  
Protein Disulfide

Calreticulin, a multi-process calcium-buffering chaperone of the endoplasmic reticulum

2009 ◽  
Vol 417 (3) ◽  
pp. 651-666 ◽  
Author(s):  
Marek Michalak ◽  
Jody Groenendyk ◽  
Eva Szabo ◽  
Leslie I. Gold ◽  
Michal Opas
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Embryonic Development ◽  
Protein Disulfide Isomerase ◽  
Biological Systems ◽  
Disulfide Isomerase ◽  
Calcium Buffering ◽  
Process Property ◽  
Protein Disulfide ◽  
Er Membrane

Calreticulin is an ER (endoplasmic reticulum) luminal Ca2+-buffering chaperone. The protein is involved in regulation of intracellular Ca2+ homoeostasis and ER Ca2+ capacity. The protein impacts on store-operated Ca2+ influx and influences Ca2+-dependent transcriptional pathways during embryonic development. Calreticulin is also involved in the folding of newly synthesized proteins and glycoproteins and, together with calnexin (an integral ER membrane chaperone similar to calreticulin) and ERp57 [ER protein of 57 kDa; a PDI (protein disulfide-isomerase)-like ER-resident protein], constitutes the ‘calreticulin/calnexin cycle’ that is responsible for folding and quality control of newly synthesized glycoproteins. In recent years, calreticulin has been implicated to play a role in many biological systems, including functions inside and outside the ER, indicating that the protein is a multi-process molecule. Regulation of Ca2+ homoeostasis and ER Ca2+ buffering by calreticulin might be the key to explain its multi-process property.

scholarly journals Protein disulfide isomerase–like proteins play opposing roles during retrotranslocation

2006 ◽  
Vol 173 (6) ◽  
pp. 853-859 ◽  
Author(s):  
Michele L. Forster ◽  
Kelsey Sivick ◽  
Young-nam Park ◽  
Peter Arvan ◽  
Wayne I. Lencer ◽  
...  
Keyword(s):  
Protein Disulfide Isomerase ◽  
Cell System ◽  
Misfolded Proteins ◽  
Toxic Agent ◽  
Er Quality Control ◽  
Disulfide Isomerase ◽  
Er Retention ◽  
Vitro Analysis ◽  
Protein Disulfide

Misfolded proteins in the endoplasmic reticulum (ER) are retained in the organelle or retrotranslocated to the cytosol for proteasomal degradation. ER chaperones that guide these opposing processes are largely unknown. We developed a semipermeabilized cell system to study the retrotranslocation of cholera toxin (CT), a toxic agent that crosses the ER membrane to reach the cytosol during intoxication. We found that protein disulfide isomerase (PDI) facilitates CT retrotranslocation, whereas ERp72, a PDI-like protein, mediates its ER retention. In vitro analysis revealed that PDI and ERp72 alter CT's conformation in a manner consistent with their roles in retrotranslocation and ER retention. Moreover, we found that PDI's and ERp72's opposing functions operate on endogenous ER misfolded proteins. Thus, our data identify PDI family proteins that play opposing roles in ER quality control and establish an assay to further delineate the mechanism of CT retrotranslocation.

scholarly journals Export of a Cysteine-Free Misfolded Secretory Protein from the Endoplasmic Reticulum for Degradation Requires Interaction with Protein Disulfide Isomerase

1999 ◽  
Vol 147 (7) ◽  
pp. 1443-1456 ◽  
Author(s):  
Pauline Gillece ◽  
José Manuel Luz ◽  
William J. Lennarz ◽  
Francisco Javier de la Cruz ◽  
Karin Römisch
Keyword(s):  
Quality Control ◽  
Protein Disulfide Isomerase ◽  
Secretory Protein ◽  
Secretory Proteins ◽  
Disulfide Isomerase ◽  
Thiol Content ◽  
Mutant Forms ◽  
Protein Disulfide ◽  
Chemical Cross Linking ◽  
Er Membrane

Protein disulfide isomerase (PDI) interacts with secretory proteins, irrespective of their thiol content, late during translocation into the ER; thus, PDI may be part of the quality control machinery in the ER. We used yeast pdi1 mutants with deletions in the putative peptide binding region of the molecule to investigate its role in the recognition of misfolded secretory proteins in the ER and their export to the cytosol for degradation. Our pdi1 deletion mutants are deficient in the export of a misfolded cysteine-free secretory protein across the ER membrane to the cytosol for degradation, but ER-to-Golgi complex transport of properly folded secretory proteins is only marginally affected. We demonstrate by chemical cross-linking that PDI specifically interacts with the misfolded secretory protein and that mutant forms of PDI have a lower affinity for this protein. In the ER of the pdi1 mutants, a higher proportion of the misfolded secretory protein remains associated with BiP, and in export-deficient sec61 mutants, the misfolded secretory protein remain bounds to PDI. We conclude that the chaperone PDI is part of the quality control machinery in the ER that recognizes terminally misfolded secretory proteins and targets them to the export channel in the ER membrane.

scholarly journals Endoplasmic Reticulum Chaperones Are Involved in the Morphogenesis of Rotavirus Infectious Particles

2008 ◽  
Vol 82 (11) ◽  
pp. 5368-5380 ◽  
Author(s):  
Liliana Maruri-Avidal ◽  
Susana López ◽  
Carlos F. Arias
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Infectious Virus ◽  
The Other ◽  
Disulfide Isomerase ◽  
Virus Particles ◽  
Final Assembly ◽  
Protein Disulfide

ABSTRACT The final assembly of rotavirus particles takes place in the endoplasmic reticulum (ER). In this work, we evaluated by RNA interference the relevance to rotavirus assembly and infectivity of grp78, protein disulfide isomerase (PDI), grp94, calnexin, calreticulin, and ERp57, members of the two ER folding systems described herein. Silencing the expression of grp94 and Erp57 had no effect on rotavirus infectivity, while knocking down the expression of any of the other four chaperons caused a reduction in the yield of infectious virus of about 50%. In grp78-silenced cells, the maturation of the oligosaccharide chains of NSP4 was retarded. In cells with reduced levels of calnexin, the oxidative folding of VP7 was impaired and the trimming of NSP4 was accelerated, and in calreticulin-silenced cells, the formation of disulfide bonds of VP7 was also accelerated. The knockdown of PDI impaired the formation and/or rearrangement of the VP7 disulfide bonds. All these conditions also affected the correct assembly of virus particles, since compared with virions from control cells, they showed an altered susceptibility to EGTA and heat treatments, a decreased specific infectivity, and a diminished reactivity to VP7 with monoclonal antibody M60, which recognizes only this protein when its disulfide bonds have been correctly formed. In the case of grp78-silenced cells, the virus produced bound less efficiently to MA104 cells than virus obtained from control cells. All these results suggest that these chaperones are involved in the quality control of rotavirus morphogenesis. The complexity of the steps of rotavirus assembly that occur in the ER provide a useful model for studying the organization and operation of the complex network of chaperones involved in maintaining the quality control of this organelle.

scholarly journals Mixed-Disulfide Folding Intermediates between Thyroglobulin and Endoplasmic Reticulum Resident Oxidoreductases ERp57 and Protein Disulfide Isomerase

2005 ◽  
Vol 25 (22) ◽  
pp. 9793-9805 ◽  
Author(s):  
Bruno Di Jeso ◽  
Young-nam Park ◽  
Luca Ulianich ◽  
A. Sonia Treglia ◽  
Malene L. Urbanas ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Disulfide Isomerase ◽  
Er Quality Control ◽  
Disulfide Isomerase ◽  
Folding Intermediates ◽  
Unfolded Protein ◽  
Mixed Disulfide ◽  
Mixed Disulfides ◽  
The Unfolded Protein Response ◽  
Protein Disulfide

ABSTRACT We present the first identification of transient folding intermediates of endogenous thyroglobulin (Tg; a large homodimeric secretory glycoprotein of thyrocytes), which include mixed disulfides with endogenous oxidoreductases servicing Tg folding needs. Formation of disulfide-linked Tg adducts with endoplasmic reticulum (ER) oxidoreductases begins cotranslationally. Inhibition of ER glucosidase activity blocked formation of a subgroup of Tg adducts containing ERp57 while causing increased Tg adduct formation with protein disulfide isomerase (PDI), delayed adduct resolution, perturbed oxidative folding of Tg monomers, impaired Tg dimerization, increased Tg association with BiP/GRP78 and GRP94, activation of the unfolded protein response, increased ER-associated degradation of a subpopulation of Tg, partial Tg escape from ER quality control with increased secretion of free monomers, and decreased overall Tg secretion. These data point towards mixed disulfides with the ERp57 oxidoreductase in conjunction with calreticulin/calnexin chaperones acting as normal early Tg folding intermediates that can be “substituted” by PDI adducts only at the expense of lower folding efficiency with resultant ER stress.

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