scholarly journals Analysis of Quality Control Substrates in Distinct Cellular Compartments Reveals a Unique Role for Rpn4p in Tolerating Misfolded Membrane Proteins

2009 ◽  
Vol 20 (3) ◽  
pp. 1006-1019 ◽  
Author(s):  
Meredith Boyle Metzger ◽  
Susan Michaelis
Keyword(s):  
Quality Control ◽  
Membrane Proteins ◽  
Transcriptional Response ◽  
Transcriptional Responses ◽  
Er Quality Control ◽  
Yeast Viability ◽  
Severe Impairment ◽  
Proteasomal Genes ◽  
The Unfolded Protein Response ◽  
Cellular Compartments

ER quality control (ERQC) prevents the exit of misfolded secretory and membrane proteins from the ER. A critical aspect of ERQC is a transcriptional response called the unfolded protein response (UPR), which up-regulates genes that enable cells to cope with misfolded, ER-retained proteins. In this study, we compare the transcriptional responses in yeast resulting from the acute expression of misfolded proteins residing in three different cellular compartments (the ER lumen, membrane, and cytosol), and find that each elicits a distinct transcriptional response. The classical UPR response, here-designated UPR-L, is induced by the ER lumenal misfolded protein, CPY*. The UPR-Cyto response is induced by the cytosolic protein, VHL-L158P, and is characterized by a rapid, transient induction of cytosolic chaperones similar to the heat-shock response. In contrast, the misfolded membrane protein with a cystolic lesion, Ste6p*, elicits a unique response designated UPR-M/C, characterized by the modest induction of >20 genes regulated by Rpn4p, an activator of proteasomal genes. Independently, we identified several genes required for yeast viability during UPR-M/C stress, but not UPR-L or UPR-Cyto stress. Among these is RPN4, highlighting the importance of the Rpn4p-dependent response in tolerating UPR-M/C stress. Further analysis suggests the requirement for Rpn4p reflects severe impairment of the proteasome by UPR-M/C stress.

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 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 Brucella effector hijacks endoplasmic reticulum quality control machinery to prevent premature egress

2019 ◽  
Author(s):  
Jean-Baptiste Luizet ◽  
Julie Raymond ◽  
Thais Lourdes Santos Lacerda ◽  
Magali Bonici ◽  
Frédérique Lembo ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
Type Iv ◽  
Endoplasmic Reticulum Quality Control ◽  
Fine Regulation ◽  
Infected Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractPerturbation of endoplasmic reticulum (ER) functions can have critical consequences for cellular homeostasis. An elaborate surveillance system known as ER quality control (ERQC) ensures that only correctly assembled proteins reach their destination. Persistence of misfolded or improperly matured proteins upregulates the unfolded protein response (UPR) to cope with stress, activates ER associated degradation (ERAD) for delivery to proteasomes for degradation. We have identified a Brucella abortus type IV secretion system effector called BspL that targets Herp, a key component of ERQC and is able to augment ERAD. Modulation of ERQC by BspL results in tight control of the kinetics of autophagic Brucella-containing vacuole formation, preventing premature bacterial egress from infected cells. This study highlights how bacterial pathogens may hijack ERAD components for fine regulation of their intracellular trafficking.

Chloroplast signaling and quality control

2017 ◽  
Vol 62 (1) ◽  
pp. 13-20 ◽  
Author(s):  
Jean-David Rochaix ◽  
Silvia Ramundo
Keyword(s):  
Quality Control ◽  
Transcriptional Response ◽  
Genetic System ◽  
Ubiquitin Proteasome System ◽  
Immune Defense ◽  
Cell Organelles ◽  
Defense Proteins ◽  
Associated Proteins ◽  
Ubiquitin Proteasome ◽  
Cellular Compartments

Although chloroplasts contain their own genetic system and are semi-autonomous cell organelles, plastid biogenesis and homeostasis are heavily dependent on the nucleo-cytosolic compartment. These two cellular compartments are closely co-ordinated through a complex signaling network comprising both anterograde and retrograde signaling chains. Developmental changes or any perturbation in the chloroplast system induced by a particular stress resulting from changes in environmental conditions such as excess light, elevated temperature, nutrient limitation, pathogen infection, give rise to specific signals. They migrate out of the chloroplast and are perceived by the nucleus where they elicit changes in expression of particular genes that allow for the maintenance of plastid homeostasis toward environmental cues. These genes mainly include those of photosynthesis-associated proteins, chaperones, proteases, nucleases and immune/defense proteins. Besides this transcriptional response, a chloroplast quality control system exists that is involved in the repair and turnover of damaged plastid proteins. This system degrades aggregated or damaged proteins and it can even remove entire chloroplasts when they have suffered heavy damage. This response comprises several processes such as plastid autophagy and ubiquitin–proteasome mediated proteolysis that occurs on the plastid envelope through the action of the ubiquitin–proteasome system.

scholarly journals Endoplasmic Reticulum Quality Control of Oligomeric Membrane Proteins: Topogenic Determinants Involved in the Degradation of the Unassembled Na,K-ATPase α Subunit and in Its Stabilization by β Subunit Assembly

2000 ◽  
Vol 11 (5) ◽  
pp. 1657-1672 ◽  
Author(s):  
Pascal Béguin ◽  
Udo Hasler ◽  
Olivier Staub ◽  
Käthi Geering
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Membrane Insertion ◽  
Membrane Domains ◽  
Related Factors ◽  
Er Quality Control ◽  
Α Subunit ◽  
Subunit Assembly ◽  
Α Subunits

The molecular nature of determinants that mediate degradation of unassembled, polytopic subunits of oligomeric membrane proteins and their stabilization after partner subunit assembly is largely unknown. Expressing truncated Na,K-ATPase α subunits alone or together with β subunits, we find that in unassembled α subunits neither the four N-terminal transmembrane segments acting as efficient alternating signal anchor–stop transfer sequences nor the large, central cytoplasmic loop exposes any degradation signal, whereas poor membrane insertion efficiency of C-terminal membrane domains M5, M7, and M9 coincides with the transient exposure of degradation signals to the cytoplasmic side. β assembly with an α domain comprising at least D902 up to Y910 in the extracytoplasmic M7/M8 loop is necessary to stabilize Na,K-ATPase α subunits by favoring M7/M8 membrane pair formation and by protecting a degradation signal recognized from the endoplasmic reticulum (ER) lumenal side. Thus our results suggest that ER degradation of Na,K-ATPase α subunits is 1) mainly mediated by folding defects caused by inefficient membrane insertion of certain membrane domains, 2) a multistep process, which involves proteolytic and/or chaperone components acting from the ER lumenal side in addition to cytosolic, proteasome-related factors, and 3) prevented by partner subunit assembly because of direct protection and retrieval of degradation signals from the cytoplasm to the ER lumenal side. These results likely represent a paradigm for the ER quality control of unassembled, polytopic subunits of oligomeric membrane proteins.

scholarly journals Lysosomal recycling of amino acids affects ER quality control

2020 ◽  
Vol 6 (26) ◽  
pp. eaaz9805
Author(s):  
Ryo Higuchi-Sanabria ◽  
Koning Shen ◽  
Naame Kelet ◽  
Phillip A. Frankino ◽  
Jenni Durieux ◽  
...  
Keyword(s):  
Amino Acids ◽  
Quality Control ◽  
Er Stress ◽  
Building Blocks ◽  
Stress Sensitivity ◽  
Loss Of Function ◽  
Er Quality Control ◽  
Glycine Metabolism ◽  
Increased Sensitivity ◽  
Cellular Compartments

Recent work has highlighted the fact that lysosomes are a critical signaling hub of metabolic processes, providing fundamental building blocks crucial for anabolic functions. How lysosomal functions affect other cellular compartments is not fully understood. Here, we find that lysosomal recycling of the amino acids lysine and arginine is essential for proper ER quality control through the UPRER. Specifically, loss of the lysine and arginine amino acid transporter LAAT-1 results in increased sensitivity to proteotoxic stress in the ER and decreased animal physiology. We find that these LAAT-1–dependent effects are linked to glycine metabolism and transport and that the loss of function of the glycine transporter SKAT-1 also increases sensitivity to ER stress. Direct lysine and arginine supplementation, or glycine supplementation alone, can ameliorate increased ER stress sensitivity found in laat-1 mutants. These data implicate a crucial role in recycling lysine, arginine, and glycine in communication between the lysosome and ER.

scholarly journals Endoplasmic Reticulum Quality Control of Unassembled Iron Transporter Depends on Rer1p-mediated Retrieval from the Golgi

2004 ◽  
Vol 15 (3) ◽  
pp. 1417-1424 ◽  
Author(s):  
Miyuki Sato ◽  
Ken Sato ◽  
Akihiko Nakano
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Model System ◽  
Er Quality Control ◽  
Iron Transporter ◽  
Er Retention ◽  
Endoplasmic Reticulum Quality Control ◽  
Sorting Receptor

Endoplasmic reticulum (ER) quality control is a conserved process by which misfolded or unassembled proteins are selectively retained in the endoplasmic reticulum (ER). Failure in oligomerization of multisubunit membrane proteins is one of the events that triggers ER quality control. The transmembrane domains (TMDs) of unassembled subunits are determinants of ER retention in many cases, although the mechanism of the TMD-mediated sorting of unassembled subunits remains elusive. We studied a yeast iron transporter complex on the cell surface as a new model system for ER quality control. When Fet3p, a transmembrane subunit, is not assembled with the other membrane subunit, Ftr1p, unassembled Fet3p is exclusively localized to the ER at steady state. The TMD of Fet3p contains a determinant for this process. However, pulse-chase analysis and in vitro budding assays indicate that unassembled Fet3p rapidly escapes from the ER. Furthermore, Rer1p, a retrieval receptor for ER-resident membrane proteins in the Golgi, is responsible for the TMD-dependent ER retrieval of unassembled Fet3p. These findings provide clear evidence that the ER quality control of unassembled membrane proteins can be achieved by retrieval from the Golgi and that Rer1p serves as a specific sorting receptor in this process.

scholarly journals Misfolded proteins are sorted by a sequential checkpoint mechanism of ER quality control

2004 ◽  
Vol 165 (1) ◽  
pp. 41-52 ◽  
Author(s):  
Shilpa Vashist ◽  
Davis T.W. Ng
Keyword(s):  
Quality Control ◽  
Membrane Proteins ◽  
Control Mechanism ◽  
Degradation Pathway ◽  
Misfolded Proteins ◽  
Er Quality Control ◽  
Golgi Transport ◽  
Test Face ◽  
Folded Proteins ◽  
Quality Control Mechanism

Misfolded proteins retained in the endoplasmic reticulum (ER) are degraded by the ER-associated degradation pathway. The mechanisms used to sort them from correctly folded proteins remain unclear. Analysis of substrates with defined folded and misfolded domains has revealed a system of sequential checkpoints that recognize topologically distinct domains of polypeptides. The first checkpoint examines the cytoplasmic domains of membrane proteins. If a lesion is detected, it is retained statically in the ER and rapidly degraded without regard to the state of its other domains. Proteins passing this test face a second checkpoint that monitors domains localized in the ER lumen. Proteins detected by this pathway are sorted from folded proteins and degraded by a quality control mechanism that requires ER-to-Golgi transport. Although the first checkpoint is obligatorily directed at membrane proteins, the second monitors both soluble and membrane proteins. Our data support a model whereby “properly folded” proteins are defined biologically as survivors that endure a series of distinct checkpoints.

scholarly journals The ART-Rsp5 ubiquitin ligase network comprises a plasma membrane quality control system that protects yeast cells from proteotoxic stress

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Yingying Zhao ◽  
Jason A MacGurn ◽  
Max Liu ◽  
Scott Emr
Keyword(s):  
Quality Control ◽  
Plasma Membrane ◽  
Control System ◽  
Membrane Proteins ◽  
Cell Surface ◽  
Ubiquitin Ligase ◽  
Integral Membrane Proteins ◽  
Quality Control System ◽  
Er Quality Control ◽  
Proteotoxic Stress

Secretory cargo that cannot fold properly in the ER are selectively targeted for removal by a well-studied ER-associated degradation pathway, or ERAD. In contrast, very little is known about post-ER quality control mechanisms for damaged or misfolded integral membrane proteins. Here we describe a quality control function of the Rsp5-ART ubiquitin ligase adaptor network that functions to protect plasma membrane (PM) integrity. Failure to mediate this protective response during heat stress leads to toxic accumulation of misfolded integral membrane proteins at the cell surface, which causes loss of PM integrity and cell death. Thus, the Rsp5-ART network comprises a PM quality control system that works together with sequential quality control pathways in the ER and Golgi to (i) target the degradation of proteins that have exceeded their functional lifetime due to damage and/or misfolding and (ii) limit the toxic accumulation of specific proteins at the cell surface during proteotoxic stress.

scholarly journals The Brucella effector BspL targets the ER-associated degradation (ERAD) pathway and delays bacterial egress from infected cells

2021 ◽  
Vol 118 (32) ◽  
pp. e2105324118
Author(s):  
Jean-Baptiste Luizet ◽  
Julie Raymond ◽  
Thais Lourdes Santos Lacerda ◽  
Emeline Barbieux ◽  
Stanimir Kambarev ◽  
...  
Keyword(s):  
Quality Control ◽  
Bacterial Pathogens ◽  
Bacterial Pathogen ◽  
Central Component ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
Control Functions ◽  
Infected Cells ◽  
The Unfolded Protein Response ◽  
Protein Response

Perturbation of the endoplasmic reticulum (ER), a central organelle of the cell, can have critical consequences for cellular homeostasis. An elaborate surveillance system known as ER quality control ensures that cells can respond and adapt to stress via the unfolded protein response (UPR) and that only correctly assembled proteins reach their destination. Interestingly, several bacterial pathogens hijack the ER to establish an infection. However, it remains poorly understood how bacterial pathogens exploit ER quality-control functions to complete their intracellular cycle. Brucella spp. replicate extensively within an ER-derived niche, which evolves into specialized vacuoles suited for exit from infected cells. Here we present Brucella-secreted protein L (BspL), a Brucella abortus effector that interacts with Herp, a central component of the ER-associated degradation (ERAD) machinery. We found that BspL enhances ERAD at the late stages of the infection. BspL targeting of Herp and ERAD allows tight control of the kinetics of autophagic Brucella-containing vacuole formation, delaying the last step of its intracellular cycle and cell-to-cell spread. This study highlights a mechanism by which a bacterial pathogen hijacks ERAD components for fine regulation of its intracellular trafficking.

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