Protein folding in the secretory pathway of animal cells

1995 ◽  
pp. 371-376
Author(s):  
Robert B. Freedman ◽  
Carole Greenall ◽  
Nigel Jenkins ◽  
Mick F. Tuite
Keyword(s):  
Protein Folding ◽  
Secretory Pathway ◽  
Animal Cells

Protein folding in the secretory pathway of animal cells

1995 ◽  
Vol 18 (1-2) ◽  
pp. 77-82 ◽  
Author(s):  
Robert B. Freedman ◽  
Carole Greenall ◽  
Nigel Jenkins ◽  
Mick F. Tuite
Keyword(s):  
Protein Folding ◽  
Secretory Pathway ◽  
Animal Cells

Quality Control and Protein Folding in the Secretory Pathway

2003 ◽  
Vol 19 (1) ◽  
pp. 649-676 ◽  
Author(s):  
E. Sergio Trombetta ◽  
Armando J. Parodi
Keyword(s):  
Quality Control ◽  
Protein Folding ◽  
Secretory Pathway

scholarly journals The Unfolded Protein Response as a Guardian of the Secretory Pathway

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2965
Author(s):  
Toni Radanović ◽  
Robert Ernst
Keyword(s):  
Protein Folding ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Unfolded Proteins ◽  
Storage Lipids ◽  
Unfolded Protein ◽  
Membrane Stiffness ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Membrane

The endoplasmic reticulum (ER) is the major site of membrane biogenesis in most eukaryotic cells. As the entry point to the secretory pathway, it handles more than 10,000 different secretory and membrane proteins. The insertion of proteins into the membrane, their folding, and ER exit are affected by the lipid composition of the ER membrane and its collective membrane stiffness. The ER is also a hotspot of lipid biosynthesis including sterols, glycerophospholipids, ceramides and neural storage lipids. The unfolded protein response (UPR) bears an evolutionary conserved, dual sensitivity to both protein-folding imbalances in the ER lumen and aberrant compositions of the ER membrane, referred to as lipid bilayer stress (LBS). Through transcriptional and non-transcriptional mechanisms, the UPR upregulates the protein folding capacity of the ER and balances the production of proteins and lipids to maintain a functional secretory pathway. In this review, we discuss how UPR transducers sense unfolded proteins and LBS with a particular focus on their role as guardians of the secretory pathway.

scholarly journals The Unfolded Protein Response: A Pathway That Links Insulin Demand with β-Cell Failure and Diabetes

2008 ◽  
Vol 29 (3) ◽  
pp. 317-333 ◽  
Author(s):  
Donalyn Scheuner ◽  
Randal J. Kaufman
Keyword(s):  
Cell Death ◽  
Protein Folding ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Cell Function ◽  
Mrna Translation ◽  
Β Cell ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response

Abstract The endoplasmic reticulum (ER) is the entry site into the secretory pathway for newly synthesized proteins destined for the cell surface or released into the extracellular milieu. The study of protein folding and trafficking within the ER is an extremely active area of research that has provided novel insights into many disease processes. Cells have evolved mechanisms to modulate the capacity and quality of the ER protein-folding machinery to prevent the accumulation of unfolded or misfolded proteins. These signaling pathways are collectively termed the unfolded protein response (UPR). The UPR sensors signal a transcriptional response to expand the ER folding capacity, increase degredation of malfolded proteins, and limit the rate of mRNA translation to reduce the client protein load. Recent genetic and biochemical evidence in both humans and mice supports a requirement for the UPR to preserve ER homeostasis and prevent the β-cell failure that may be fundamental in the etiology of diabetes. Chronic or overwhelming ER stress stimuli associated with metabolic syndrome can disrupt protein folding in the ER, reduce insulin secretion, invoke oxidative stress, and activate cell death pathways. Therapeutic interventions to prevent polypeptide-misfolding, oxidative damage, and/or UPR-induced cell death have the potential to improve β-cell function and/or survival in the treatment of diabetes.

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 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.

scholarly journals The Unfolded Protein Response as Guardian of the Secretory Pathway

2021 ◽  
Author(s):  
Toni Radanović ◽  
Robert Ernst
Keyword(s):  
Protein Folding ◽  
Unfolded Protein Response ◽  
Secretory Pathway ◽  
Membrane Lipids ◽  
Unfolded Proteins ◽  
Storage Lipids ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Membrane

The endoplasmic reticulum (ER) is the major site of membrane biogenesis in most eukaryotic cells. As the entry point to the secretory pathway, it handles more than 10.000 different secretory and membrane proteins. The membrane insertion of proteins, their folding, and ER exit are affected by the lipid composition of the ER membrane and its collective membrane stiffness. The ER is also a hotspot of lipid metabolism for membrane lipids including sterols, glycerophospholipids, ceramides and neural storage lipids. The unfolded protein response (UPR) bears an evolutionary conserved, dual sensitivity to both protein folding-imbalances in the ER lumen and aberrant compositions of the ER membrane, referred to as lipid bilayer stress (LBS). Through transcriptional and non-transcriptional mechanisms, the UPR upregulates the protein folding capacity of the ER and balances the production of proteins and lipids to maintain a functional secretory pathway. In this review, we discuss how UPR transducers sense unfolded proteins and LBS with a particular focus on their role as guardians of the secretory pathway.

scholarly journals Functional identification of a Streptomyces lividans FKBP-like protein involved in the folding of overproduced secreted proteins

Open Biology ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 190201
Author(s):  
R. L. Vicente ◽  
S. Marín ◽  
J. R. Valverde ◽  
C. Palomino ◽  
R. P. Mellado ◽  
...  
Keyword(s):  
Protein Folding ◽  
Secretory Pathway ◽  
Streptomyces Lividans ◽  
Secretory Protein ◽  
Industrial Applications ◽  
Secreted Proteins ◽  
Secretory Proteins ◽  
Heterologous Proteins ◽  
Functional Identification ◽  
Ppiase Activity

Some bacterial peptidyl-prolyl cis/trans isomerases (PPIases) are involved in secretory protein folding after the translocation step. Streptomyces lividans has been used as a host for engineering extracellular overproduction of homologous and heterologous proteins in industrial applications. Although the mechanisms governing the major secretory pathway (Sec route) and the minor secretory pathway (Tat route) are reasonably well described, the function of proteins responsible for the extracellular secretory protein folding is not characterized as yet. We have characterized a Tat-dependent S . lividans FK506-binding protein-like lipoprotein (FKBP) that has PPIase activity. A mutant in the sli-fkbp gene induces a secretion stress response and affects secretion and activity of the Sec-dependent protein α-amylase. Additionally, propagation in high copy number of the sli-fkbp gene has a positive effect on the activity of both the overproduced α-amylase and the overproduced Tat-dependent agarase, both containing proline cis isomers. Targeted proteomic analyses showed that a relevant group of secreted proteins in S. lividans TK21 are affected by Sli-FKBP, revealing a wide substrate range. The results obtained indicate that, regardless of the secretory route used by proteins in S. lividans , adjusting the expression of sli-fkbp may facilitate folding of dependent proteins when engineering Streptomyces strains for the overproduction of homologous or heterologous secretory proteins.

The Functional Competence of Animal Cells: Anal Ysis of the Secretory Pathway

2005 ◽  
pp. 71-74
Author(s):  
Daniel E. Alete ◽  
Andrew J. Racher ◽  
John R. Birch ◽  
David C. James ◽  
C. Mark Smales
Keyword(s):  
Secretory Pathway ◽  
Animal Cells ◽  
Functional Competence ◽  
Anal Ysis

scholarly journals A Homolog of Voltage-Gated Ca2+Channels Stimulated by Depletion of Secretory Ca2+ in Yeast

2000 ◽  
Vol 20 (18) ◽  
pp. 6686-6694 ◽  
Author(s):  
Emily G. Locke ◽  
Myriam Bonilla ◽  
Linda Liang ◽  
Yoko Takita ◽  
Kyle W. Cunningham
Keyword(s):  
Mammalian Cells ◽  
Secretory Pathway ◽  
Uptake System ◽  
Wild Type ◽  
Animal Cells ◽  
Voltage Gated ◽  
High Affinity ◽  
Essential Components ◽  
Yeast Mutants ◽  
Stimulation Of

ABSTRACT In animal cells, capacitative calcium entry (CCE) mechanisms become activated specifically in response to depletion of calcium ions (Ca2+) from secretory organelles. CCE serves to replenish those organelles and to enhance signaling pathways that respond to elevated free Ca2+ concentrations in the cytoplasm. The mechanism of CCE regulation is not understood because few of its essential components have been identified. We show here for the first time that the budding yeast Saccharomyces cerevisiaeemploys a CCE-like mechanism to refill Ca2+ stores within the secretory pathway. Mutants lacking Pmr1p, a conserved Ca2+ pump in the secretory pathway, exhibit higher rates of Ca2+ influx relative to wild-type cells due to the stimulation of a high-affinity Ca2+ uptake system. Stimulation of this Ca2+ uptake system was blocked inpmr1 mutants by expression of mammalian SERCA pumps. The high-affinity Ca2+ uptake system was also stimulated in wild-type cells overexpressing vacuolar Ca2+ transporters that competed with Pmr1p for substrate. A screen for yeast mutants specifically defective in the high-affinity Ca2+ uptake system revealed two genes, CCH1 and MID1, previously implicated in Ca2+ influx in response to mating pheromones. Cch1p and Mid1p were localized to the plasma membrane, coimmunoprecipitated from solubilized membranes, and shown to function together within a single pathway that ensures that adequate levels of Ca2+ are supplied to Pmr1p to sustain secretion and growth. Expression of Cch1p and Mid1p was not affected in pmr1mutants. The evidence supports the hypothesis that yeast maintains a homeostatic mechanism related to CCE in mammalian cells. The homology between Cch1p and the catalytic subunit of voltage-gated Ca2+ channels raises the possibility that in some circumstances CCE in animal cells may involve homologs of Cch1p and a conserved regulatory mechanism.

Sign in / Sign up

Export Citation Format

Share Document