scholarly journals The Targeting of Native Proteins to the Endoplasmic Reticulum-Associated Degradation (ERAD) Pathway: An Expanding Repertoire of Regulated Substrates

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1185
Author(s):  
Deepa Kumari ◽  
Jeffrey L. Brodsky
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Integral Membrane Proteins ◽  
Protein Substrates ◽  
Native Proteins ◽  
The Many ◽  
Erad Pathway ◽  
Solute Transporters

All proteins are subject to quality control processes during or soon after their synthesis, and these cellular quality control pathways play critical roles in maintaining homeostasis in the cell and in organism health. Protein quality control is particularly vital for those polypeptides that enter the endoplasmic reticulum (ER). Approximately one-quarter to one-third of all proteins synthesized in eukaryotic cells access the ER because they are destined for transport to the extracellular space, because they represent integral membrane proteins, or because they reside within one of the many compartments of the secretory pathway. However, proteins that mature inefficiently are subject to ER-associated degradation (ERAD), a multi-step pathway involving the chaperone-mediated selection, ubiquitination, and extraction (or “retrotranslocation”) of protein substrates from the ER. Ultimately, these substrates are degraded by the cytosolic proteasome. Interestingly, there is an increasing number of native enzymes and metabolite and solute transporters that are also targeted for ERAD. While some of these proteins may transiently misfold, the ERAD pathway also provides a route to rapidly and quantitatively downregulate the levels and thus the activities of a variety of proteins that mature or reside in the ER.

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.

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 Crosstalk between Endoplasmic Reticulum Stress and Protein Misfolding in Neurodegenerative Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-22 ◽  
Author(s):  
Cláudia M. F. Pereira
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Prion Diseases ◽  
Protein Quality Control ◽  
Subcellular Compartment ◽  
Novel Therapeutic Strategies

Under physiological conditions, the endoplasmic reticulum (ER) is a central subcellular compartment for protein quality control in the secretory pathway that prevents protein misfolding and aggregation. Instrumental in protein quality control in the ER is the unfolded protein response (UPR), which is activated upon ER stress to reestablish homeostasis through a sophisticated transcriptionally and translationally regulated signaling network. However, this response can lead to apoptosis if the stress cannot be alleviated. The presence of abnormal protein aggregates containing specific misfolded proteins is recognized as the basis of numerous human conformational disorders, including neurodegenerative diseases. Here, I will highlight the overwhelming evidence that the presence of specific aberrant proteins in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), prion diseases, and Amyotrophic Lateral Sclerosis (ALS) is intimately associated with perturbations in the ER protein quality control machinery that become incompetent to restore protein homeostasis and shift adaptive programs toward the induction of apoptotic signaling to eliminate irreversibly damaged neurons. Increasing our understanding about the deadly crosstalk between ER dysfunction and protein misfolding in these neurodegenerative diseases may stimulate the development of novel therapeutic strategies able to support neuronal survival and ameliorate disease progression.

scholarly journals In and Out of the ER: Protein Folding, Quality Control, Degradation, and Related Human Diseases

2007 ◽  
Vol 87 (4) ◽  
pp. 1377-1408 ◽  
Author(s):  
Daniel N. Hebert ◽  
Maurizio Molinari
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Molecular Chaperones ◽  
Secretory Pathway ◽  
Human Diseases ◽  
Gene Products ◽  
Substantial Fraction ◽  
Native Proteins ◽  
Eukaryotic Gene ◽  
Er Membrane

A substantial fraction of eukaryotic gene products are synthesized by ribosomes attached at the cytosolic face of the endoplasmic reticulum (ER) membrane. These polypeptides enter cotranslationally in the ER lumen, which contains resident molecular chaperones and folding factors that assist their maturation. Native proteins are released from the ER lumen and are transported through the secretory pathway to their final intra- or extracellular destination. Folding-defective polypeptides are exported across the ER membrane into the cytosol and destroyed. Cellular and organismal homeostasis relies on a balanced activity of the ER folding, quality control, and degradation machineries as shown by the dozens of human diseases related to defective maturation or disposal of individual polypeptides generated in the ER.

scholarly journals Chaperone-Mediated Reflux of Secretory Proteins to the Cytosol During Endoplasmic Reticulum Stress

2019 ◽  
Author(s):  
Aeid Igbaria ◽  
Philip I. Merksamer ◽  
Ala Trusina ◽  
Firehiwot Tilahun ◽  
Jefferey R. Johnson ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Fluorescent Protein ◽  
Control Process ◽  
Secretory Proteins ◽  
Er Quality Control ◽  
Quality Control Process

ABSTRACTDiverse perturbations to endoplasmic reticulum (ER) functions compromise the proper folding and structural maturation of secretory proteins. To study secretory pathway physiology during such “ER stress”, we employed an ER-targeted, redox-responsive, green fluorescent protein—eroGFP—that reports on ambient changes in oxidizing potential. Here we find that diverse ER stress agents cause properly folded, ER-resident eroGFP (and other ER luminal proteins) to “reflux” back to the reducing environment of the cytosol as intact, folded proteins. By utilizing eroGFP in a comprehensive genetic screen in S. cerevisiae, we show that ER protein reflux during ER stress requires specific chaperones and co-chaperones residing in both the ER and the cytosol. Chaperone-mediated ER protein reflux does not require E3 ligase activity, and proceeds even more vigorously when these ER-associated degradation (ERAD) factors are crippled, suggesting that reflux may work in parallel with ERAD. In summary, chaperone-mediated ER-protein reflux may be a conserved protein quality control process that evolved to maintain secretory pathway homeostasis during ER protein-folding stress.SIGNIFICANCEApproximately one third of eukaryotic proteins are synthesized on ribosomes attached to the endoplasmic reticulum (ER) membrane. Many of these polypeptides co- or post-translationally translocate into the ER, wherein they fold and mature. An ER quality-control system proofreads these proteins by facilitating their folding and modification, while eliminating misfolded proteins through ER-associated degradation (ERAD). Yet, the fate of many secretory proteins during ER stress is not completely understood. Here, we uncovered an ER-stress induced “protein reflux” system that delivers intact, folded ER luminal proteins back to the cytosol without degrading them. We found that ER protein reflux works in parallel to ERAD and requires distinct ER-resident and cytosolic chaperones and co-chaperones.

scholarly journals Endoplasmic Reticulum-Mediated Protein Quality Control and Endoplasmic Reticulum-Associated Degradation Pathway Explain the Reduction of N-glycoprotein Level Under the Lead Stress

2021 ◽  
Vol 11 ◽  
Author(s):  
Hong Du ◽  
Canqi Zheng ◽  
Muhmmad Aslam ◽  
Xihui Xie ◽  
Wanna Wang ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Level ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Misfolded Proteins ◽  
Pb Stress ◽  
Endoplasmic Reticulum Associated Degradation ◽  
High Lead ◽  
Erad Pathway

Different anthropogenic activities result in the continuous increase of metal lead (Pb) in the environment and adversely affect living organisms. Therefore, it is important to investigate the tolerance mechanism in a model organism. Chlamydomonas reinhardtii is an important green eukaryotic model microalga for studying different kinds of biological questions. In this study, the responses of C. reinhardtii were revealed via a comprehensive approach, including physiological, genomic, transcriptomic, glycomic, and bioinformatic techniques. Physiological results showed that the growth rate and soluble protein content were significantly reduced under the high lead stress. Also, the results obtained from the genomic and transcriptomic analyses presented that the endoplasmic reticulum-mediated protein quality control (ERQC) system and endoplasmic reticulum-associated degradation (ERAD) pathway were activated under the third day of high lead stress. The unique upregulated protein disulfide isomerase genes on the ERQC system were proposed to be important for the protein level and protein quality control. The accumulation of specific N-glycans indicated that specific N-glycosylation of proteins might alter the biological functions of proteins to alleviate the Pb stress in alga and/or lead to the degradation of incomplete/misfolded proteins. At the same time, it was observed that genes involved in each process of ERAD were upregulated, suggesting that the ERAD pathway was activated to assist the degradation of incomplete/misfolded proteins. Therefore, it is reasonable to speculate that the reduction of protein level under the high lead stress was related to the activated ERQC system and QRAD pathway. Our findings will provide a solid and reliable foundation and a proposed ERAD working model for further in-depth study of the ERQC system and ERAD pathway under the Pb stress and even other biotic and abiotic stresses.

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.

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