scholarly journals Extracellular Secretion of Overexpressed Glycosylphosphatidylinositol-Linked Cell Wall Protein Utr2/Crh2p as a Novel Protein Quality Control Mechanism in Saccharomyces cerevisiae

2010 ◽  
Vol 9 (11) ◽  
pp. 1669-1679 ◽  
Author(s):  
Kelly A. Miller ◽  
Louis DiDone ◽  
Damian J. Krysan
Keyword(s):  
Quality Control ◽  
Cell Wall ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Cell Wall Protein ◽  
Content Type ◽  
Unfolded Protein ◽  
Extracellular Secretion ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACT Eukaryotic cells employ a variety of mechanisms to maintain protein quality control and homeostasis. Here we provide evidence that one such mechanism in Saccharomyces cerevisiae involves the regulated release of excess or misfolded proteins to the extracellular space. The overexpression of an epitope-tagged allele of the glycosylphosphatidylinositol (GPI)-linked cell wall protein Utr2/Crh2p (Utr2/Crh2-green fluorescent protein [GFP] or -hemagglutinin [HA]) causes endoplasmic reticulum (ER) stress and the secretion of Crh2-GFP/HA into the extracellular space. Secretion is dependent on two GPI-linked aspartyl proteases (Yps1p/2p) and components of the unfolded protein response (Ire1p and Hac1p) but is independent of ER-associated degradation (ERAD) components such as Hrd1p and Doa10p. Supporting the idea that this process represents a mechanism for protein quality control, the level of Crh2-HA is increased in strains lacking Bst1p, a protein required for the proteasomal degradation of GPI-linked proteins. Furthermore, secretion is dependent on Sec18p, indicating that it requires ER-to-Golgi trafficking, and accordingly, Crh2-HA accumulates in the ER in ire1Δ and bst1Δ mutants by cycloheximide chase experiments. Since a fraction of Utr2/Crh2-GFP properly localizes to the cell wall in an ire1Δ mutant, extracellular secretion appears to occur through a pathway that is distinct from the normal GPI protein-trafficking pathway. Taken together, these data support a model in which the unfolded protein response (UPR)/yapsin-mediated extracellular release of overexpressed Utr2/Crh2-HA or -GFP is an alternative pathway for the removal of excess or misfolded secretory proteins functioning in parallel with proteasome-mediated degradation in S. cerevisiae. This model provides an explanation for the deleterious effects of Yps1/2p on the industrial production of some recombinant proteins in S. cerevisiae.

scholarly journals Modulating protein quality control

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Lars Plate ◽  
Ryan J Paxman ◽  
R Luke Wiseman ◽  
Jeffery W Kelly
Keyword(s):  
Quality Control ◽  
Small Molecules ◽  
Unfolded Protein Response ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Misfolding Diseases ◽  
Protein Response

Small molecules that modulate the unfolded protein response have the potential to treat a variety of human protein misfolding diseases.

scholarly journals Protein quality control in the secretory pathway

2019 ◽  
Vol 218 (10) ◽  
pp. 3171-3187 ◽  
Author(s):  
Zhihao Sun ◽  
Jeffrey L. Brodsky
Keyword(s):  
Quality Control ◽  
Protein Folding ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Misfolded Proteins ◽  
Unfolded Protein ◽  
Protein Biogenesis ◽  
The Unfolded Protein Response ◽  
Protein Response

Protein folding is inherently error prone, especially in the endoplasmic reticulum (ER). Even with an elaborate network of molecular chaperones and protein folding facilitators, misfolding can occur quite frequently. To maintain protein homeostasis, eukaryotes have evolved a series of protein quality-control checkpoints. When secretory pathway quality-control pathways fail, stress response pathways, such as the unfolded protein response (UPR), are induced. In addition, the ER, which is the initial hub of protein biogenesis in the secretory pathway, triages misfolded proteins by delivering substrates to the proteasome or to the lysosome/vacuole through ER-associated degradation (ERAD) or ER-phagy. Some misfolded proteins escape the ER and are instead selected for Golgi quality control. These substrates are targeted for degradation after retrieval to the ER or delivery to the lysosome/vacuole. Here, we discuss how these guardian pathways function, how their activities intersect upon induction of the UPR, and how decisions are made to dispose of misfolded proteins in the secretory pathway.

LonP1 Links UPRmt and UPRER to Regulate Heart Function

2021 ◽  
Author(s):  
Yujie Li ◽  
Dawei Huang ◽  
Fugen Shangguan ◽  
Lianqun Jia ◽  
Linhua Lan ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Heart Function ◽  
Mitochondrial Dynamics ◽  
Protein Quality Control ◽  
Metabolic Reprogramming ◽  
The Novel ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract Protein quality control is pivotal to cellular homeostasis and integrity of cardiomyocytes for maintenance of normal heart function. The unfolded protein response (UPR) is an adaptive process to modulate protein quality control in the endoplasmic reticulum (ER) and mitochondria, and is accordingly termed UPRER and UPRmt, respectively. Lon protease (LonP1) is a highly conserved mitochondrial protease to modulate UPRmt, which is involved in regulating metabolism, mitophagy, and stress response. However, whether LonP1 regulates UPRER remains elusive. To investigate the regulation of protein quality control in cardiomyocytes, we generated cardiac-specific LonP1 deletion mice. Our findings show that LonP1 deficiency caused impaired mitochondrial respiratory function and fragmentation. Surprisingly, both UPRER and UPRmt is substantially induced in LonP1-deletion heart suggesting of LonP1 as a novel regulator of UPRER; however, the activation of UPRER occurs earlier than UPRmt in response to LonP1 deletion. Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming of cardiomyocytes, pathological heart remodeling, as well as impeded heart function. We uncovered the novel function of LonP1 as an UPRmt mediator, and reciprocal orchestration of UPRmt and UPRER and mitochondrial dynamics regulated by LonP1 in the cardiomyocytes that is critical to maintain heart function, which offers exciting new insights into the potential therapeutic strategy for heart failure.

scholarly journals LonP1 Orchestrates UPRmtand UPRERand Mitochondrial Dynamics to Regulate Heart Function

2019 ◽  
Author(s):  
Bin Lu ◽  
Fugen Shangguan ◽  
Dawei Huang ◽  
Shiwei Gong ◽  
Yingchao Shi ◽  
...  
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Heart Function ◽  
Mitochondrial Dynamics ◽  
Protein Quality Control ◽  
Metabolic Reprogramming ◽  
The Novel ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractProtein quality control is pivotal to cellular homeostasis and integrity of cardiomyocytes for maintenance of normal heart function. The unfolded protein response (UPR) is an adaptive process to modulate protein quality control in the endoplasmic reticulum (ER) and mitochondria, and is accordingly termed UPRERand UPRmt, respectively. Lon protease (LonP1) is a highly conserved mitochondrial protease to modulate UPRmt, which is involved in regulating metabolism, mitophagy, and stress response. However, whether LonP1 regulates UPRERremains elusive. To investigate the regulation of protein quality control in cardiomyocytes, we generated cardiac-specific LonP1 deletion mice. Our findings show that LonP1 deficiency caused impaired mitochondrial respiratory function and fragmentation. Surprisingly, both UPRERand UPRmtis substantially induced in LonP1-deletion heart suggesting of LonP1 as a novel regulator of UPRER; however, the activation of UPRERoccurs earlier than UPRmtin response to LonP1 deletion. Consequently, cardiac-specific LonP1 deficiency causes aberrant metabolic reprogramming of cardiomyocytes, pathological heart remodeling, as well as impeded heart function. Thus, we uncovered the novel function of LonP1 as an UPRmtmediator, and reciprocal orchestration of UPRmtand UPRERand mitochondrial dynamics regulated by LonP1 in the cardiomyocytes that is critical to maintain heart function, which offers exciting new insights into the potential therapeutic strategy for heart failure.

scholarly journals The UPR in Neurodegenerative Disease: Not Just an Inside Job

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1090
Author(s):  
Anna Maria van Ziel ◽  
Wiep Scheper
Keyword(s):  
Quality Control ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Long Distance ◽  
Unfolded Protein ◽  
Long Distance Transport ◽  
Cell Type Specific ◽  
Membrane Bound ◽  
The Unfolded Protein Response ◽  
Protein Response

Neurons are highly specialized cells that continuously and extensively communicate with other neurons, as well as glia cells. During their long lifetime, the post-mitotic neurons encounter many stressful situations that can disrupt protein homeostasis (proteostasis). The importance of tight protein quality control is illustrated by neurodegenerative disorders where disturbed neuronal proteostasis causes neuronal dysfunction and loss. For their unique function, neurons require regulated and long-distance transport of membrane-bound cargo and organelles. This highlights the importance of protein quality control in the neuronal endomembrane system, to which the unfolded protein response (UPR) is instrumental. The UPR is a highly conserved stress response that is present in all eukaryotes. However, recent studies demonstrate the existence of cell-type-specific aspects of the UPR, as well as cell non-autonomous UPR signaling. Here we discuss these novel insights in view of the complex cellular architecture of the brain and the implications for neurodegenerative diseases.

Protein quality control at the mitochondrion

2016 ◽  
Vol 60 (2) ◽  
pp. 213-225 ◽  
Author(s):  
Wolfgang Voos ◽  
Witold Jaworek ◽  
Anne Wilkening ◽  
Michael Bruderek
Keyword(s):  
Quality Control ◽  
Structural Integrity ◽  
Protein Quality ◽  
Mitochondrial Protein ◽  
Protein Quality Control ◽  
Eukaryotic Cell ◽  
Control Mechanisms ◽  
Biochemical Processes ◽  
Unfolded Protein ◽  
Protein Response

Mitochondria are essential constituents of a eukaryotic cell by supplying ATP and contributing to many mayor metabolic processes. As endosymbiotic organelles, they represent a cellular subcompartment exhibiting many autonomous functions, most importantly containing a complete endogenous machinery responsible for protein expression, folding and degradation. This article summarizes the biochemical processes and the enzymatic components that are responsible for maintaining mitochondrial protein homoeostasis. As mitochondria lack a large part of the required genetic information, most proteins are synthesized in the cytosol and imported into the organelle. After reaching their destination, polypeptides must fold and assemble into active proteins. Under pathological conditions, mitochondrial proteins become misfolded or damaged and need to be repaired with the help of molecular chaperones or eventually removed by specific proteases. Failure of these protein quality control mechanisms results in loss of mitochondrial function and structural integrity. Recently, novel mechanisms have been identified that support mitochondrial quality on the organellar level. A mitochondrial unfolded protein response allows the adaptation of chaperone and protease activities. Terminally damaged mitochondria may be removed by a variation of autophagy, termed mitophagy. An understanding of the role of protein quality control in mitochondria is highly relevant for many human pathologies, in particular neurodegenerative diseases.

Repression of N-glycosylation triggers the unfolded protein response (UPR) and overexpression of cell wall protein and chitin in Aspergillus fumigatus

Microbiology ◽  
2011 ◽  
Vol 157 (7) ◽  
pp. 1968-1979 ◽  
Author(s):  
Kai Li ◽  
Haomiao Ouyang ◽  
Yang Lü ◽  
Jingnan Liang ◽  
Iain B. H. Wilson ◽  
...  
Keyword(s):  
Cell Wall ◽  
Aspergillus Fumigatus ◽  
Unfolded Protein Response ◽  
Cell Wall Protein ◽  
Signalling Pathway ◽  
Cell Wall Biosynthesis ◽  
Unfolded Protein ◽  
Cell Wall Biogenesis ◽  
The Unfolded Protein Response ◽  
Protein Response

Aspergillus fumigatus is the most common airborne fungal pathogen, causing fatal invasive aspergillosis in immunocompromised patients. The crude mortality is 60–90 % and remains around 29–42 % even with treatment. The main reason for patient death is the low efficiency of the drug therapies. As protein N-glycosylation is involved in cell wall biogenesis in A. fumigatus, a deeper understanding of its role in cell wall biogenesis will help to develop new drug targets. The Afstt3 gene encodes the essential catalytic subunit of oligosaccharyltransferase, an enzyme complex responsible for the transfer of the N-glycan to nascent polypeptides. To evaluate the role of N-glycosylation in cell wall biosynthesis, we constructed the conditional mutant strain CPR-stt3 by replacing the endogenous promoter of Afstt3 with the nitrogen-dependent niiA promoter. Repression of the Afstt3 gene in the CPR-stt3 strain led to a severe retardation of growth and a slight defect in cell wall integrity (CWI). One of the most interesting findings was that upregulation of the cell wall-related genes was not accompanied by an activation of the MpkA kinase, which has been shown to be a central element in the CWI signalling pathway in both Saccharomyces cerevisiae and A. fumigatus. Considering that the unfolded protein response (UPR) was found to be activated, which might upregulate the expression of cell wall protein and chitin, our data suggest that the UPR, instead of the MpkA-dependent CWI signalling pathway, is the major compensatory mechanism induced by repression but not abolition of N-glycosylation in A. fumigatus. Our finding is a key to understanding the complex compensatory mechanisms of cell wall biosynthesis and may provide a new strategy for drug development.

scholarly journals Possible involvement of endoplasmic reticulum stress in the pathogenesis of Alzheimer’s disease

2015 ◽  
Vol 2 (1) ◽  
Author(s):  
Toru Hosoi ◽  
Jun Nomura ◽  
Koichiro Ozawa ◽  
Akinori Nishi ◽  
Yasuyuki Nomura
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Protein Quality ◽  
Unfolded Proteins ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe endoplasmic reticulum (ER) is an organelle that plays a crucial role in protein quality control such as protein folding. Evidence to indicate the involvement of ER in maintaining cellular homeostasis is increasing. However, when cells are exposed to stressful conditions, which perturb ER function, unfolded proteins accumulate leading to ER stress. Cells then activate the unfolded protein response (UPR) to cope with this stressful condition. In the present review, we will discuss and summarize recent advances in research on the basic mechanisms of the UPR. We also discuss the possible involvement of ER stress in the pathogenesis of Alzheimer’s disease (AD). Potential therapeutic opportunities for diseases targeting ER stress is also described.

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