scholarly journals Golgi-Mediated Vacuolar Sorting of the Endoplasmic Reticulum Chaperone BiP May Play an Active Role in Quality Control within the Secretory Pathway

2005 ◽  
Vol 18 (1) ◽  
pp. 198-211 ◽  
Author(s):  
Peter Pimpl ◽  
J. Philip Taylor ◽  
Christopher Snowden ◽  
Stefan Hillmer ◽  
David G. Robinson ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Active Role ◽  
Vacuolar Sorting ◽  
Endoplasmic Reticulum Chaperone

scholarly journals Regulation and Quality Control of Adiponectin Assembly by Endoplasmic Reticulum Chaperone ERp44

2015 ◽  
Vol 290 (29) ◽  
pp. 18111-18123 ◽  
Author(s):  
Lutz Hampe ◽  
Mazdak Radjainia ◽  
Cheng Xu ◽  
Paul W. R. Harris ◽  
Ghader Bashiri ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Chaperone

scholarly journals Activation of Mammalian Unfolded Protein Response Is Compatible with the Quality Control System Operating in the Endoplasmic Reticulum

2004 ◽  
Vol 15 (6) ◽  
pp. 2537-2548 ◽  
Author(s):  
Satomi Nadanaka ◽  
Hiderou Yoshida ◽  
Fumi Kano ◽  
Masayuki Murata ◽  
Kazutoshi Mori
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Control System ◽  
Golgi Apparatus ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
Protein Response

Newly synthesized secretory and transmembrane proteins are folded and assembled in the endoplasmic reticulum (ER) where an efficient quality control system operates so that only correctly folded molecules are allowed to move along the secretory pathway. The productive folding process in the ER has been thought to be supported by the unfolded protein response (UPR), which is activated by the accumulation of unfolded proteins in the ER. However, a dilemma has emerged; activation of ATF6, a key regulator of mammalian UPR, requires intracellular transport from the ER to the Golgi apparatus. This suggests that unfolded proteins might be leaked from the ER together with ATF6 in response to ER stress, exhibiting proteotoxicity in the secretory pathway. We show here that ATF6 and correctly folded proteins are transported to the Golgi apparatus via the same route and by the same mechanism under conditions of ER stress, whereas unfolded proteins are retained in the ER. Thus, activation of the UPR is compatible with the quality control in the ER and the ER possesses a remarkable ability to select proteins to be transported in mammalian cells in marked contrast to yeast cells, which actively utilize intracellular traffic to deal with unfolded proteins accumulated in the ER.

scholarly journals Aberrant substrate engagement of the ER translocon triggers degradation by the Hrd1 ubiquitin ligase

2012 ◽  
Vol 197 (6) ◽  
pp. 761-773 ◽  
Author(s):  
Eric M. Rubenstein ◽  
Stefan G. Kreft ◽  
Wesley Greenblatt ◽  
Robert Swanson ◽  
Mark Hochstrasser
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Membrane Protein ◽  
Ubiquitin Ligase ◽  
Apolipoprotein B ◽  
Secretory Pathway ◽  
Protein A ◽  
Proteasomal Degradation ◽  
Membrane Localization ◽  
General Role

Little is known about quality control of proteins that aberrantly or persistently engage the endoplasmic reticulum (ER)-localized translocon en route to membrane localization or the secretory pathway. Hrd1 and Doa10, the primary ubiquitin ligases that function in ER-associated degradation (ERAD) in yeast, target distinct subsets of misfolded or otherwise abnormal proteins based primarily on degradation signal (degron) location. We report the surprising observation that fusing Deg1, a cytoplasmic degron normally recognized by Doa10, to the Sec62 membrane protein rendered the protein a Hrd1 substrate. Hrd1-dependent degradation occurred when Deg1-Sec62 aberrantly engaged the Sec61 translocon channel and underwent topological rearrangement. Mutations that prevent translocon engagement caused a reversion to Doa10-dependent degradation. Similarly, a variant of apolipoprotein B, a protein known to be cotranslocationally targeted for proteasomal degradation, was also a Hrd1 substrate. Hrd1 therefore likely plays a general role in targeting proteins that persistently associate with and potentially obstruct the translocon.

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.

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.

Calnexin: a molecular chaperone with a taste for carbohydrate

1995 ◽  
Vol 73 (3-4) ◽  
pp. 123-132 ◽  
Author(s):  
David B. Williams
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Molecular Chaperone ◽  
Molecular Chaperones ◽  
Secretory Pathway ◽  
Quaternary Structure ◽  
Integral Membrane Protein ◽  
Secretory Proteins ◽  
Chaperone Function ◽  
Folded Proteins

Calnexin is an integral membrane protein of the endoplasmic reticulum (ER) that binds transiently to a wide array of newly synthesized membrane and secretory proteins. It also exhibits prolonged binding to misfolded or incompletely folded proteins. Recent studies have demonstrated that calnexin functions as a molecular chaperone to facilitate the folding and assembly of proteins in the ER. It is also a component of the quality control system that prevents proteins from progressing along the secretory pathway until they have acquired proper tertiary or quaternary structure. Most proteins that are translocated into the ER are glycosylated at Asn residues, and calnexin's interactions are almost exclusively restricted to proteins that possess this posttranslational modification. The preference for glycoproteins resides in calnexin's ability to function as a lectin with specificity for the GlC1Man9GlcNAc2 oligosaccharide, an early intermediate in the processing of Asn-linked oligosaccharides. Calnexin also has the capacity to bind to polypeptide segments of unfolded glycoproteins. Available evidence suggests that calnexin utilizes its lectin property during initial capture of a newly synthesized glycoprotein and that subsequent association (and chaperone function) is mediated through polypeptide interactions. Unlike other molecular chaperones that are soluble proteins, calnexin is an intrinsic component of the ER membrane. Its unique ability to capture unfolded glycoproteins through their large oligosaccharide moieties may have evolved as a means to overcome accessibility problems imposed by being constrained within a lipid bilayer.Key words: protein folding, molecular chaperones, calnexin, quality control, endoplasmic reticulum.

Protein quality control at the endoplasmic reticulum

2016 ◽  
Vol 60 (2) ◽  
pp. 227-235 ◽  
Author(s):  
Kathleen McCaffrey ◽  
Ineke Braakman
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Bond Formation ◽  
Protein Quality Control ◽  
Secretory Proteins ◽  
Protein Quality Control System ◽  
And Function ◽  
Extracellular Environment

The ER (endoplasmic reticulum) is the protein folding ‘factory’ of the secretory pathway. Virtually all proteins destined for the plasma membrane, the extracellular space or other secretory compartments undergo folding and maturation within the ER. The ER hosts a unique PQC (protein quality control) system that allows specialized modifications such as glycosylation and disulfide bond formation essential for the correct folding and function of many secretory proteins. It is also the major checkpoint for misfolded or aggregation-prone proteins that may be toxic to the cell or extracellular environment. A failure of this system, due to aging or other factors, has therefore been implicated in a number of serious human diseases. In this article, we discuss several key features of ER PQC that maintain the health of the cellular secretome.

scholarly journals Quality Control in the Secretory Pathway: The Role of Calreticulin, Calnexin and BiP in the Retention of Glycoproteins with C-Terminal Truncations

1997 ◽  
Vol 8 (10) ◽  
pp. 1943-1954 ◽  
Author(s):  
Jian-Xin Zhang ◽  
Ineke Braakman ◽  
Kent E.S. Matlack ◽  
Ari Helenius
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Disulfide Bonds ◽  
Mammalian Cells ◽  
Secretory Pathway ◽  
Influenza Hemagglutinin ◽  
Culture Cells ◽  
Folded Structure ◽  
Low Concentrations ◽  
Sorting Process

Unlike properly folded and assembled proteins, most misfolded and incompletely assembled proteins are retained in the endoplasmic reticulum of mammalian cells and degraded without transport to the Golgi complex. To analyze the mechanisms underlying this unique sorting process and its fidelity, the fate of C-terminally truncated fragments of influenza hemagglutinin was determined. An assortment of different fragments was generated by adding puromycin at low concentrations to influenza virus-infected tissue culture cells. Of the fragments generated, <2% was secreted, indicating that the system for detecting defects in newly synthesized proteins is quite stringent. The majority of secreted species corresponded to folding domains within the viral spike glycoprotein. The retained fragments acquired a partially folded structure with intrachain disulfide bonds and conformation-dependent antigenic epitopes. They associated with two lectin-like endoplasmic reticulum chaperones (calnexin and calreticulin) but not BiP/GRP78. Inhibition of the association with calnexin and calreticulin by the addition of castanospermine significantly increased fragment secretion. However, it also caused association with BiP/GRP78. These results indicated that the association with calnexin and calreticulin was involved in retaining the fragments. They also suggested that BiP/GRP78 could serve as a backup for calnexin and calreticulin in retaining the fragments. In summary, the results showed that the quality control system in the secretory pathway was efficient and sensitive to folding defects, and that it involved multiple interactions with endoplasmic reticulum chaperones.

scholarly journals A Novel Quality Control Compartment Derived from the Endoplasmic Reticulum

2001 ◽  
Vol 12 (6) ◽  
pp. 1711-1723 ◽  
Author(s):  
Shiri Kamhi-Nesher ◽  
Marina Shenkman ◽  
Sandra Tolchinsky ◽  
Sharon Vigodman Fromm ◽  
Rachel Ehrlich ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Brefeldin A ◽  
Degradation Process ◽  
Transmembrane Conductance Regulator ◽  
Heavy Chains ◽  
Tightly Coupled ◽  
Ubiquitin Proteasome ◽  
Control Compartment

Degradation of proteins that, because of improper or suboptimal processing, are retained in the endoplasmic reticulum (ER) involves retrotranslocation to reach the cytosolic ubiquitin-proteasome machinery. We found that substrates of this pathway, the precursor of human asialoglycoprotein receptor H2a and free heavy chains of murine class I major histocompatibility complex (MHC), accumulate in a novel preGolgi compartment that is adjacent to but not overlapping with the centrosome, the Golgi complex, and the ER-to-Golgi intermediate compartment (ERGIC). On its way to degradation, H2a associated increasingly after synthesis with the ER translocon Sec61. Nevertheless, it remained in the secretory pathway upon proteasomal inhibition, suggesting that its retrotranslocation must be tightly coupled to the degradation process. In the presence of proteasomal inhibitors, the ER chaperones calreticulin and calnexin, but not BiP, PDI, or glycoprotein glucosyltransferase, concentrate in the subcellular region of the novel compartment. The “quality control” compartment is possibly a subcompartment of the ER. It depends on microtubules but is insensitive to brefeldin A. We discuss the possibility that it is also the site for concentration and retrotranslocation of proteins that, like the mutant cystic fibrosis transmembrane conductance regulator, are transported to the cytosol, where they form large aggregates, the “aggresomes.”

scholarly journals A post-ER degradation pathway that relies on protease-dependent internalization from the vacuolar membrane

2019 ◽  
Author(s):  
Leticia Lemus ◽  
Zrinka Matić ◽  
Veit Goder
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Proteolytic Activity ◽  
Secretory Pathway ◽  
Model Organism ◽  
Degradation Pathway ◽  
Vacuolar Membrane ◽  
List Type ◽  
Er Quality Control

SummaryNewly synthesized proteins of the secretory pathway are quality-controlled inside the endoplasmic reticulum (ER) and, if not properly folded, are retained. An exception are glycosylphosphatidylinositol-anchored proteins (GPI-APs) which can leave the ER even when misfolded and are routed to the vacuole/lysosome for degradation by largely unknown mechanisms linked to post-ER quality control. Using yeast as model organism, we show that Gas1*, an ER-exported misfolded GPI-AP, is diverted from the secretory pathway to endosomes for transport to the vacuole. However, Gas1* is not sorted into endosomal intraluminal vesicles but internalizes directly from the vacuolar membrane. There, the vacuolar protease Pep4, but not any other known vacuolar protease, is required for Gas1* internalization. Our data reveal novel and unexpected mechanisms for invaginations from the vacuolar membrane.HighlightsER-exited misfolded GPI-anchored proteins are routed to the vacuole via endosomes but do not internalize into intraluminal vesiclesInternalization occurs directly from the vacuolar membrane into intravacuolar mobile structuresInternalization from the vacuolar membrane depends on the proteolytic activity of the vacuolar protease Pep4

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