scholarly journals The Delicate Balance Between Secreted Protein Folding and Endoplasmic Reticulum-Associated Degradation in Human Physiology

2012 ◽  
Vol 92 (2) ◽  
pp. 537-576 ◽  
Author(s):  
Christopher J. Guerriero ◽  
Jeffrey L. Brodsky
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Protein Function ◽  
Secretory Pathway ◽  
Secretory Protein ◽  
Disease Treatment ◽  
Discovery Research ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Erad Pathway ◽  
By Products

Protein folding is a complex, error-prone process that often results in an irreparable protein by-product. These by-products can be recognized by cellular quality control machineries and targeted for proteasome-dependent degradation. The folding of proteins in the secretory pathway adds another layer to the protein folding “problem,” as the endoplasmic reticulum maintains a unique chemical environment within the cell. In fact, a growing number of diseases are attributed to defects in secretory protein folding, and many of these by-products are targeted for a process known as endoplasmic reticulum-associated degradation (ERAD). Since its discovery, research on the mechanisms underlying the ERAD pathway has provided new insights into how ERAD contributes to human health during both normal and diseases states. Links between ERAD and disease are evidenced from the loss of protein function as a result of degradation, chronic cellular stress when ERAD fails to keep up with misfolded protein production, and the ability of some pathogens to coopt the ERAD pathway. The growing number of ERAD substrates has also illuminated the differences in the machineries used to recognize and degrade a vast array of potential clients for this pathway. Despite all that is known about ERAD, many questions remain, and new paradigms will likely emerge. Clearly, the key to successful disease treatment lies within defining the molecular details of the ERAD pathway and in understanding how this conserved pathway selects and degrades an innumerable cast of substrates.

scholarly journals Organizational Diversity among Distinct Glycoprotein Endoplasmic Reticulum-associated Degradation Programs

2002 ◽  
Vol 13 (8) ◽  
pp. 2639-2650 ◽  
Author(s):  
Christopher M. Cabral ◽  
Yan Liu ◽  
Kelley W. Moremen ◽  
Richard N. Sifers
Keyword(s):  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Degradation Process ◽  
Secretory Protein ◽  
Human Embryonic Kidney ◽  
Apparent Lack ◽  
Human Embryonic Kidney Cells ◽  
Early Secretory Pathway ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Pathway Function

Protein folding and quality control in the early secretory pathway function as posttranslational checkpoints in eukaryote gene expression. Herein, an aberrant form of the hepatic secretory protein α1-antitrypsin was stably expressed in a human embryonic kidney cell line to elucidate the mechanisms by which glycoprotein endoplasmic reticulum-associated degradation (GERAD) is administered in cells from higher eukaryotes. After biosynthesis, genetic variant PI Z underwent alternative phases of secretion and degradation, the latter of which was mediated by the proteasome. Degradation required release from calnexin- and asparagine-linked oligosaccharide modification by endoplasmic reticulum mannosidase I, the latter of which occurred as PI Z was bound to the molecular chaperone grp78/BiP. That a distinct GERAD program operates in human embryonic kidney cells was supported by the extent of PI Z secretion, apparent lack of polymerization, inability of calnexin to participate in the degradation process, and sequestration of the glycoprotein folding sensor UDP-glucose:glycoprotein glucosyltransferase in the Golgi complex. Because UDP-glucose:glycoprotein glucosyltransferase sustains calnexin binding, its altered distribution is consistent with a GERAD program that hinders the reentry of substrates into the calnexin cycle, allowing grp78/BiP to partner with a lectin, other than calnexin, in the recognition of a two-component GERAD signal to facilitate substrate recruitment. How the processing of a mutant protein, rather than the mutation itself, can contribute to disease pathogenesis, is discussed.

scholarly journals Reduction of HIV-1 Infectivity through Endoplasmic Reticulum-Associated Degradation-Mediated Env Depletion

2014 ◽  
Vol 89 (5) ◽  
pp. 2966-2971 ◽  
Author(s):  
Antonio Casini ◽  
Michele Olivieri ◽  
Lara Vecchi ◽  
Oscar R. Burrone ◽  
Anna Cereseto
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Viral Production ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Viral Particles ◽  
Erad Pathway ◽  
System Operating ◽  
Hiv 1 ◽  
Replicative Cycle

During the HIV-1 replicative cycle, the gp160 envelope is processed in the secretory pathway to mature into the gp41 and gp120 subunits. Misfolded proteins located within the endoplasmic reticulum (ER) are proteasomally degraded through the ER-associated degradation (ERAD) pathway, a quality control system operating in this compartment. Here, we exploited the ERAD pathway to induce the degradation of gp160 during viral production, thus leading to the release of gp120-depleted viral particles.

scholarly journals SLC26A9 is selected for endoplasmic reticulum associated degradation (ERAD) via Hsp70-dependent targeting of the soluble STAS domain

2021 ◽  
Author(s):  
Patrick G Needham ◽  
Jennifer L Goeckeler-Fried ◽  
Casey Zhang ◽  
Zhihao Sun ◽  
Adam R Wetzel ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Ion Channels ◽  
Membrane Protein ◽  
Secretory Pathway ◽  
Expression System ◽  
Chloride Ions ◽  
Substrate Selection ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Stas Domain

SLC26A9, a member of the solute carrier protein family, transports chloride ions across various epithelia. SLC26A9 also associates with other ion channels and transporters linked to human health, and in some cases these heterotypic interactions are essential to support the biogenesis of both proteins. Therefore, understanding how this complex membrane protein is initially folded might provide new therapeutic strategies to overcome deficits in the function of SLC26A9 partners, one of which is associated with Cystic Fibrosis. To this end, we developed a novel yeast expression system for SLC26A9. This facile system has been used extensively with other ion channels and transporters to screen for factors that oversee protein folding checkpoints. As commonly observed for other channels and transporters, we first noted that a substantial fraction of SLC26A9 is targeted for endoplasmic reticulum associated degradation (ERAD), which destroys folding-compromised proteins in the early secretory pathway. We next discovered that ERAD selection requires the Hsp70 chaperone, which can play a vital role in ERAD substrate selection. We then created SLC26A9 mutants and found that the transmembrane-rich domain of SLC26A9 was quite stable, whereas the soluble cytosolic STAS domain was responsible for Hsp70-dependent ERAD. To support data obtained in the yeast model, we were able to recapitulate Hsp70-facilitated ERAD of the STAS domain in human tissue culture cells. These results indicate that a critical barrier to nascent membrane protein folding can reside within a specific soluble domain, one that is monitored by components associated with the ERAD machinery.

Spatial localization of unknown proteins in the endoplasmic reticulum predicts functions

2007 ◽  
Vol 30 (4) ◽  
pp. 84
Author(s):  
Michael D. Jain ◽  
Hisao Nagaya ◽  
Annalyn Gilchrist ◽  
Miroslaw Cygler ◽  
John J.M. Bergeron
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Protein Synthesis ◽  
Protein Function ◽  
Protein Translocation ◽  
Spatial Localization ◽  
Predict Protein Function ◽  
Insight Into ◽  
Soluble Fractions ◽  
Er Membrane

Protein synthesis, folding and degradation functions are spatially segregated in the endoplasmic reticulum (ER) with respect to the membrane and the ribosome (rough and smooth ER). Interrogation of a proteomics resource characterizing rough and smooth ER membranes subfractionated into cytosolic, membrane, and soluble fractions gives a spatial map of known proteins involved in ER function. The spatial localization of 224 identified unknown proteins in the ER is predicted to give insight into their function. Here we provide evidence that the proteomics resource accurately predicts the function of new proteins involved in protein synthesis (nudilin), protein translocation across the ER membrane (nicalin), co-translational protein folding (stexin), and distal protein folding in the lumen of the ER (erlin-1, TMX2). Proteomics provides the spatial localization of proteins and can be used to accurately predict protein function.

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 New Mutants of Saccharomyces cerevisiae Affected in the Transport of Proteins From the Endoplasmic Reticulum to the Golgi Complex

Genetics ◽  
1996 ◽  
Vol 142 (2) ◽  
pp. 393-406 ◽  
Author(s):  
Linda J Wuestehube ◽  
Rainer Duden ◽  
Arlene Eun ◽  
Susan Hamamoto ◽  
Paul Korn ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Golgi Complex ◽  
Secretory Pathway ◽  
Secretory Protein ◽  
Temperature Sensitive ◽  
Nonpermissive Temperature ◽  
Membrane Structures ◽  
Α Subunit ◽  
Complementation Groups ◽  
Vacuolar Protein

Abstract We have isolated new temperature-sensitive mutations in five complementation groups, sec31-sec35, that are defective in the transport of proteins from the endoplasmic reticulum (ER) to the Golgi complex. The sec31-sec35 mutants and additional alleles of previously identified sec and vacuolar protein sorting (vps) genes were isolated in a screen based on the detection of α-factor precursor in yeast colonies replicated to and lysed on nitrocellulose filters. Secretory protein precursors accumulated in sec31-sec35 mutants at the nonpermissive temperature were core-glycosylated but lacked outer chain carbohydrate, indicating that transport was blocked after translocation into the ER but before arrival in the Golgi complex. Electron microscopy revealed that the newly identified sec mutants accumulated vesicles and membrane structures reminiscent of secretory pathway organelles. Complementation analysis revealed that sec32-1 is an allele of BOS1, a gene implicated in vesicle targeting to the Golgi complex, and sec33-1 is an allele of RET1, a gene that encodes the α subunit of coatomer.

scholarly journals Erv14p Directs a Transmembrane Secretory Protein into COPII-coated Transport Vesicles

2002 ◽  
Vol 13 (3) ◽  
pp. 880-891 ◽  
Author(s):  
Jacqueline Powers ◽  
Charles Barlowe
Keyword(s):  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Integral Membrane Protein ◽  
Secretory Protein ◽  
Conserved Residues ◽  
Early Secretory Pathway ◽  
Transport Vesicles ◽  
Copii Vesicle ◽  
Copii Vesicles ◽  
Selection Of

Erv14p is a conserved integral membrane protein that traffics in COPII-coated vesicles and localizes to the early secretory pathway in yeast. Deletion of ERV14 causes a defect in polarized growth because Axl2p, a transmembrane secretory protein, accumulates in the endoplasmic reticulum and is not delivered to its site of function on the cell surface. Herein, we show that Erv14p is required for selection of Axl2p into COPII vesicles and for efficient formation of these vesicles. Erv14p binds to subunits of the COPII coat and binding depends on conserved residues in a cytoplasmically exposed loop domain of Erv14p. When mutations are introduced into this loop, an Erv14p-Axl2p complex accumulates in the endoplasmic reticulum, suggesting that Erv14p links Axl2p to the COPII coat. Based on these results and further genetic experiments, we propose Erv14p coordinates COPII vesicle formation with incorporation of specific secretory cargo.

scholarly journals Approaches to imaging unfolded secretory protein stress in living cells

2014 ◽  
Vol 1 (1) ◽  
Author(s):  
Patrick Lajoie ◽  
Elena N. Fazio ◽  
Erik L. Snapp
Keyword(s):  
Quality Control ◽  
Signaling Pathways ◽  
Protein Function ◽  
Secretory Pathway ◽  
Transcriptional Response ◽  
Secretory Protein ◽  
Model Systems ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
Point Of Entry

AbstractThe endoplasmic reticulum (ER) is the point of entry of proteins into the secretory pathway. Nascent peptides interact with the ER quality control machinery that ensures correct folding of the nascent proteins. Failure to properly fold proteins can lead to loss of protein function and cytotoxic aggregation of misfolded proteins that can lead to cell death. To cope with increases in the ER unfolded secretory protein burden, cells have evolved the Unfolded Protein Response (UPR). The UPR is the primary signaling pathway that monitors the state of the ER folding environment. When the unfolded protein burden overwhelms the capacity of the ER quality control machinery, a state termed ER stress, sensor proteins detect accumulation of misfolded peptides and trigger the UPR transcriptional response. The UPR, which is conserved from yeast to mammals, consists of an ensemble of complex signaling pathways that aims at adapting the ER to the new misfolded protein load. To determine how different factors impact the ER folding environment, various tools and assays have been developed. In this review, we discuss recent advances in live cell imaging reporters and model systems that enable researchers to monitor changes in the unfolded secretory protein burden and activation of the UPR and its associated signaling pathways.

scholarly journals A Striking Quality Control Subcompartment in Saccharomyces cerevisiae: The Endoplasmic Reticulum-associated Compartment

2004 ◽  
Vol 15 (2) ◽  
pp. 908-921 ◽  
Author(s):  
Gregory Huyer ◽  
Gaby L. Longsworth ◽  
Deborah L. Mason ◽  
Monica P. Mallampalli ◽  
J. Michael McCaffery ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Secretory Pathway ◽  
Secretory Protein ◽  
Cellular Functions ◽  
Er Quality Control ◽  
Fluorescence And Electron Microscopy ◽  
The Unfolded Protein Response ◽  
Mutant Forms

The folding of nascent secretory and membrane proteins is monitored by the endoplasmic reticulum (ER) quality control system. Misfolded proteins are retained in the ER and can be removed by ER-associated degradation. As a model for the ER quality control of multispanning membrane proteins in yeast, we have been studying mutant forms of Ste6p. Here, we identify mislocalized mutant forms of Ste6p that induce the formation of, and localize to, prominent structures that are absent in normal cells. We have named these structures ER-associated compartments (ERACs), based on their juxtaposition to and connection with the ER, as observed by fluorescence and electron microscopy. ERACs comprise a network of tubulo-vesicular structures that seem to represent proliferated ER membranes. Resident ER lumenal and membrane proteins are present in ERACs in addition to their normal ER localization, suggesting there is no barrier for their entry into ERACs. However, the forms of Ste6p in ERACs are excluded from the ER and do not enter the secretory pathway; instead, they are ultimately targeted for ER-associated degradation. The presence of ERACs does not adversely affect secretory protein traffic through the ER and does not lead to induction of the unfolded protein response. We propose that ERACs may be holding sites to which misfolded membrane proteins are specifically diverted so as not to interfere with normal cellular functions. We discuss the likelihood that related ER membrane proliferations that form in response to certain other mutant or unassembled membrane proteins may be substantially similar to ERACs.

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