scholarly journals Ubiquitination in the ERAD Process

2020 ◽  
Vol 21 (15) ◽  
pp. 5369
Author(s):  
Anna Lopata ◽  
Andreas Kniss ◽  
Frank Löhr ◽  
Vladimir V. Rogov ◽  
Volker Dötsch
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
The Other ◽  
Misfolded Protein ◽  
E3 Ligases ◽  
Aaa Atpase ◽  
A Cell ◽  
Conjugating Enzymes ◽  
The One ◽  
Erad Pathway

In this review, we focus on the ubiquitination process within the endoplasmic reticulum associated protein degradation (ERAD) pathway. Approximately one third of all synthesized proteins in a cell are channeled into the endoplasmic reticulum (ER) lumen or are incorporated into the ER membrane. Since all newly synthesized proteins enter the ER in an unfolded manner, folding must occur within the ER lumen or co-translationally, rendering misfolding events a serious threat. To prevent the accumulation of misfolded protein in the ER, proteins that fail the quality control undergo retrotranslocation into the cytosol where they proceed with ubiquitination and degradation. The wide variety of misfolded targets requires on the one hand a promiscuity of the ubiquitination process and on the other hand a fast and highly processive mechanism. We present the various ERAD components involved in the ubiquitination process including the different E2 conjugating enzymes, E3 ligases, and E4 factors. The resulting K48-linked and K11-linked ubiquitin chains do not only represent a signal for degradation by the proteasome but are also recognized by the AAA+ ATPase Cdc48 and get in the process of retrotranslocation modified by enzymes bound to Cdc48. Lastly we discuss the conformations adopted in particular by K48-linked ubiquitin chains and their importance for degradation.

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.

scholarly journals Overlapping function of Hrd1 and Ste24 in translocon quality control provides robust channel surveillance

2020 ◽  
Vol 295 (47) ◽  
pp. 16113-16120
Author(s):  
Avery M. Runnebohm ◽  
Kyle A. Richards ◽  
Courtney Broshar Irelan ◽  
Samantha M. Turk ◽  
Halie E. Vitali ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Ubiquitin Ligase ◽  
Biological Membranes ◽  
The Other ◽  
Growth Defect ◽  
Zinc Metalloprotease

Translocation of proteins across biological membranes is essential for life. Proteins that clog the endoplasmic reticulum (ER) translocon prevent the movement of other proteins into the ER. Eukaryotes have multiple translocon quality control (TQC) mechanisms to detect and destroy proteins that persistently engage the translocon. TQC mechanisms have been defined using a limited panel of substrates that aberrantly occupy the channel. The extent of substrate overlap among TQC pathways is unknown. In this study, we found that two TQC enzymes, the ER-associated degradation ubiquitin ligase Hrd1 and zinc metalloprotease Ste24, promote degradation of characterized translocon-associated substrates of the other enzyme in Saccharomyces cerevisiae. Although both enzymes contribute to substrate turnover, our results suggest a prominent role for Hrd1 in TQC. Yeast lacking both Hrd1 and Ste24 exhibit a profound growth defect, consistent with overlapping function. Remarkably, two mutations that mildly perturb post-translational translocation and reduce the extent of aberrant translocon engagement by a model substrate diminish cellular dependence on TQC enzymes. Our data reveal previously unappreciated mechanistic complexity in TQC substrate detection and suggest that a robust translocon surveillance infrastructure maintains functional and efficient translocation machinery.

scholarly journals Processing and Analysis of Long-Range Scans with an Atomic Force Microscope (AFM) in Combination with Nanopositioning and Nanomeasuring Technology for Defect Detection and Quality Control

Sensors ◽  
2021 ◽  
Vol 21 (17) ◽  
pp. 5862
Author(s):  
Ingo Ortlepp ◽  
Jaqueline Stauffenberg ◽  
Eberhard Manske
Keyword(s):  
Quality Control ◽  
High Resolution ◽  
Atomic Force Microscope ◽  
Range Of Motion ◽  
Defect Detection ◽  
Large Range ◽  
The Other ◽  
Atomic Force ◽  
Measuring Machine ◽  
The One

This paper deals with a planar nanopositioning and -measuring machine, the so-called nanofabrication machine (NFM-100), in combination with a mounted atomic force microscope (AFM). This planar machine has a circular moving range of 100 mm. Due to the possibility of detecting structures in the nanometre range with an atomic force microscope and the large range of motion of the NFM-100, structures can be analysed with high resolution and precision over large areas by combining the two systems, which was not possible before. On the basis of a grating sample, line scans over lengths in the millimetre range are demonstrated on the one hand; on the other hand, the accuracy as well as various evaluation methods are discussed and analysed.

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.

scholarly journals XXVII.—On the Restoration of Co-ordinated Movements after Nerve Section

1900 ◽  
Vol 39 (3) ◽  
pp. 685-702 ◽  
Author(s):  
Robert Kennedy
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Point Of View ◽  
The Other ◽  
Nerve Fibres ◽  
Spinal Root ◽  
A Cell ◽  
The Central Nervous System ◽  
The One ◽  
The Individual

From the point of view of its function, a nerve fibre is a conductor of nervous impulses, and as such is the path of communication between two structures, the one situated in the central nervous system, and the other in the periphery. In the mixed nerve, such as the sciatic, the nerve fibres are distinguished as afferent or as efferent, according as they conduct impulses originating at the periphery, and received by a cell in the central nervous system, or vice versâ. It has long since been shown that nerve fibres are capable of conducting impulses in either direction, but normally, from their anatomical connections, the individual nerve fibres are conductors for impulses only in the one or in the other direction. This is proved by the Wallerian method of investigation, as on severance of the posterior spinal root distal to the ganglion only certain fibres degenerate and the conductivity of the nerve only for afferent impulses is lost, while the severance of the anterior root is followed by the degeneration of the remainder with loss of functions depending on efferent impulses.

Studies in calcium-caseinogen equilibria, and their bearing on the secretion of calcium in milk. (preliminary paper.)

1926 ◽  
Vol 16 (4) ◽  
pp. 640-642 ◽  
Author(s):  
Norman Charles Wright
Keyword(s):  
Cell Membrane ◽  
The Other ◽  
Unequal Distribution ◽  
Selective Action ◽  
Selective Permeability ◽  
A Cell ◽  
The One

Two fundamental explanations have been advanced to account for the unequal distribution of electrolytes on either side of a cell membrane: the one bases the unequal distribution on the existence of a cell membrane of so-called selective permeability, by which the membrane is endowed with the property of presenting varying resistance to the passage of different ions; the other regards the unequal distribution as being due to the selective action of the cell constituents themselves. This latter theory regards the cell primarily as a system in which the distribution of electrolytes is governed by the equilibrium existing on either side of a membrane permeable to electrolytes but impermeable to other ionised constituents of the cell.

scholarly journals Endoplasmic Reticulum Chaperones Are Involved in the Morphogenesis of Rotavirus Infectious Particles

2008 ◽  
Vol 82 (11) ◽  
pp. 5368-5380 ◽  
Author(s):  
Liliana Maruri-Avidal ◽  
Susana López ◽  
Carlos F. Arias
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Infectious Virus ◽  
The Other ◽  
Disulfide Isomerase ◽  
Virus Particles ◽  
Final Assembly ◽  
Protein Disulfide

ABSTRACT The final assembly of rotavirus particles takes place in the endoplasmic reticulum (ER). In this work, we evaluated by RNA interference the relevance to rotavirus assembly and infectivity of grp78, protein disulfide isomerase (PDI), grp94, calnexin, calreticulin, and ERp57, members of the two ER folding systems described herein. Silencing the expression of grp94 and Erp57 had no effect on rotavirus infectivity, while knocking down the expression of any of the other four chaperons caused a reduction in the yield of infectious virus of about 50%. In grp78-silenced cells, the maturation of the oligosaccharide chains of NSP4 was retarded. In cells with reduced levels of calnexin, the oxidative folding of VP7 was impaired and the trimming of NSP4 was accelerated, and in calreticulin-silenced cells, the formation of disulfide bonds of VP7 was also accelerated. The knockdown of PDI impaired the formation and/or rearrangement of the VP7 disulfide bonds. All these conditions also affected the correct assembly of virus particles, since compared with virions from control cells, they showed an altered susceptibility to EGTA and heat treatments, a decreased specific infectivity, and a diminished reactivity to VP7 with monoclonal antibody M60, which recognizes only this protein when its disulfide bonds have been correctly formed. In the case of grp78-silenced cells, the virus produced bound less efficiently to MA104 cells than virus obtained from control cells. All these results suggest that these chaperones are involved in the quality control of rotavirus morphogenesis. The complexity of the steps of rotavirus assembly that occur in the ER provide a useful model for studying the organization and operation of the complex network of chaperones involved in maintaining the quality control of this organelle.

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 Cooperation of mitochondrial and ER factors in quality control of tail-anchored proteins

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Verena Dederer ◽  
Anton Khmelinskii ◽  
Anna Gesine Huhn ◽  
Voytek Okreglak ◽  
Michael Knop ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Ubiquitin Ligase ◽  
Mitochondrial Membrane ◽  
E3 Ubiquitin Ligase ◽  
Outer Mitochondrial Membrane ◽  
Complex Assembly ◽  
Aaa Atpase ◽  
Er Targeting ◽  
Ta Proteins

Tail-anchored (TA) proteins insert post-translationally into the endoplasmic reticulum (ER), the outer mitochondrial membrane (OMM) and peroxisomes. Whereas the GET pathway controls ER-targeting, no dedicated factors are known for OMM insertion, posing the question of how accuracy is achieved. The mitochondrial AAA-ATPase Msp1 removes mislocalized TA proteins from the OMM, but it is unclear, how Msp1 clients are targeted for degradation. Here we screened for factors involved in degradation of TA proteins mislocalized to mitochondria. We show that the ER-associated degradation (ERAD) E3 ubiquitin ligase Doa10 controls cytoplasmic level of Msp1 clients. Furthermore, we identified the uncharacterized OMM protein Fmp32 and the ectopically expressed subunit of the ER-mitochondria encounter structure (ERMES) complex Gem1 as native clients for Msp1 and Doa10. We propose that productive localization of TA proteins to the OMM is ensured by complex assembly, while orphan subunits are extracted by Msp1 and eventually degraded by Doa10.

scholarly journals Protein synthesis by membrane-bound and free ribosomes of secretory and non-secretory tissues

1971 ◽  
Vol 121 (4) ◽  
pp. 683-694 ◽  
Author(s):  
T. M. Andrews ◽  
J. R. Tata
Keyword(s):  
Endoplasmic Reticulum ◽  
Messenger Rna ◽  
Sodium Deoxycholate ◽  
The Other ◽  
Separation Procedure ◽  
Membrane Bound ◽  
The One ◽  
Almost All

1. Methods for the separation of membrane-bound and free ribosomes from rat brain (cortex) and skeletal muscle were described and the preparations characterized by chemical analysis and electron microscopy. The attachment of ribosomes to membranes is not an artifact of the separation procedure. 2. The rate of incorporation of l-[14C]leucine into protein in vitro by the membrane-bound and free ribosomes from these two predominantly non-protein-secreting tissues is compared with that by similar preparations from rat liver. With all three tissues the initial rate was higher for the membrane-bound preparations. 3. By using the technique of discharging nascent polypeptide chains by incubation with puromycin followed by treatment with sodium deoxycholate (Redman & Sabatini, 1966), a major difference was observed for the vectorial discharge of nascent protein synthesized both in vivo and in vitro on membrane-bound ribosomes from liver, on the one hand, and brain and muscle, on the other. Whereas a large part of nascent protein synthesized on membrane-bound liver ribosomes was discharged into the membranous vesicles (presumably destined for export from the cell), almost all nascent protein from membrane-bound ribosomes from brain and muscle was released directly into the supernatant. Incorporation of [3H]puromycin into peptidyl-[3H]puromycin confirmed these findings. There was thus no difference between membrane-bound and free ribosomes from brain on the one hand, and from free polyribosomes from liver on the other, as far as the vectorial release of newly synthesized protein was concerned. 4. Incubation with puromycin also showed that the nascent chains, pre-formed in vivo and in vitro, are not involved in the attachment of ribosomes to membranes of the endoplasmic reticulum. 5. The differences in vectorial discharge from membrane-bound ribosomes from liver as compared with brain and muscle are not due to the different types of messenger RNA in the different tissues. Polyphenylalanine synthesized on incubation with polyuridylic acid was handled in the same way as polypeptides synthesized with endogenous messenger. 6. It is concluded that there is a major difference in the attachment of ribosomes to the membranes of the endoplasmic reticulum of secretory and non-secretory tissues, which results in a tissue-specific difference in the vectorial discharge of nascent proteins.

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