Redox diversity in ERAD-mediated protein retrotranslocation from the endoplasmic reticulum: a complex puzzle

2015 ◽  
Vol 396 (5) ◽  
pp. 539-554 ◽  
Author(s):  
Yutaka Suzuki ◽  
Manfred J. Schmitt
Keyword(s):  
Endoplasmic Reticulum ◽  
Host Cell ◽  
Secretory Pathway ◽  
Redox Status ◽  
Current View ◽  
Cell Penetration ◽  
Protein Toxins ◽  
Underlying Mechanisms ◽  
Disulfide Isomerization

Abstract Misfolded and incorrectly assembled proteins in the secretory pathway are eliminated by ubiquitylation and proteasomal degradation in a process known as ER-associated degradation (ERAD). Retrotranslocation of diverse substrates including misfolded proteins and viruses occurs through channels in the ER membrane, which are also utilized for host cell penetration by A/B class protein toxins such as cholera toxin, ricin or K28. According to the current view, disulfide-bonded proteins must either be reduced or rearranged to ensure translocation competence and entry into the cytosol from the ER. As the underlying mechanisms are still largely mysterious, we here focus on the redox status and disulfide isomerization of ERAD substrates and the role of oxidoreductases in the essential process of ER-to-cytosol retrotranslocation.

Peroxisomal membrane proteins are properly targeted to peroxisomes in the absence of COPI- and COPII-mediated vesicular transport

2001 ◽  
Vol 114 (11) ◽  
pp. 2199-2204 ◽  
Author(s):  
Tineke Voorn-Brouwer ◽  
Astrid Kragt ◽  
Henk F. Tabak ◽  
Ben Distel
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Secretory Pathway ◽  
Human Fibroblasts ◽  
Vesicle Transport ◽  
Peroxisome Biogenesis ◽  
Peroxisomal Membrane ◽  
Classic Model ◽  
Early Secretory Pathway

The classic model for peroxisome biogenesis states that new peroxisomes arise by the fission of pre-existing ones and that peroxisomal matrix and membrane proteins are recruited directly from the cytosol. Recent studies challenge this model and suggest that some peroxisomal membrane proteins might traffic via the endoplasmic reticulum to peroxisomes. We have studied the trafficking in human fibroblasts of three peroxisomal membrane proteins, Pex2p, Pex3p and Pex16p, all of which have been suggested to transit the endoplasmic reticulum before arriving in peroxisomes. Here, we show that targeting of these peroxisomal membrane proteins is not affected by inhibitors of COPI and COPII that block vesicle transport in the early secretory pathway. Moreover, we have obtained no evidence for the presence of these peroxisomal membrane proteins in compartments other than peroxisomes and demonstrate that COPI and COPII inhibitors do not affect peroxisome morphology or integrity. Together, these data fail to provide any evidence for a role of the endoplasmic reticulum in peroxisome biogenesis.

scholarly journals Apoptosis-Associated Speck-Like Protein Containing a CARD Deletion Ameliorates Unilateral Ureteral Obstruction Induced Renal Fibrosis and Endoplasmic Reticulum Stress in Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Yao Xu ◽  
Yuqing Liu ◽  
Honglei Guo ◽  
Wei Ding
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Pathological Feature ◽  
Ureter Obstruction ◽  
Underlying Mechanisms ◽  
Stage Renal Disease ◽  
End Stage

Inflammation might be one of the essential underlying mechanisms of renal fibrosis, which is considered a key pathological feature of end-stage renal disease and is closely associated with proteinuria and decreased renal function. Apoptosis-associated speck-like protein containing a CARD (ASC), identified as the central structure of inflammasome, is involved in the progression of interstitial fibrosis; however, its signal transduction pathways remain unclear. In the present study, we performed unilateral ureter obstruction (UUO) in both wild-type and ASC deletion mice to determine the contribution of ASC to renal fibrosis. Compared with control groups, UUO significantly induced renal fibrosis and collagen deposition, as evidenced by photomicrographs. ASC deletion attenuated renal injury, reduced cell infiltration and the release of inflammatory cytokines, protected against apoptosis, and downregulated the PRKR-like endoplasmic reticulum kinase (PERK) pathway of endoplasmic reticulum (ER) stress. Our data identify a novel role of ASC in the regulation of renal fibrosis and ER stress after UUO, strongly indicating that ASC could serve as an attractive target in the treatment of chronic kidney disease.

scholarly journals Wolbachia endosymbionts subvert the endoplasmic reticulum to acquire host membranes without triggering ER stress

2018 ◽  
Author(s):  
Nour Fattouh ◽  
Chantal Cazevieille ◽  
Frédéric Landmann
Keyword(s):  
Endoplasmic Reticulum ◽  
Golgi Apparatus ◽  
Host Cell ◽  
Pathogenic Bacteria ◽  
Secretory Pathway ◽  
Immune Surveillance ◽  
Lipid Synthesis ◽  
Time Lapse ◽  
Intracellular Bacteria ◽  
Arthropod Species

AbstractThe reproductive parasite Wolbachia are the most common endosymbionts on earth, present in a plethora of arthropod species. They have been introduced into mosquitos to successfully prevent the spread of vector-borne diseases, yet the strategies of host cell subversion underlying their obligate intracellular lifestyle remain to be explored in depth in order to gain insights into the mechanisms of pathogen-blocking. Like some other intracellular bacteria, Wolbachia reside in a host-derived vacuole in order to replicate and escape the immune surveillance. Using here the pathogen-blocking Wolbachia strain from Drosophila melanogaster, introduced into two different Drosophila cell lines, we show that Wolbachia subvert the endoplasmic reticulum to acquire their vacuolar membrane and colonize the host cell at high density. Wolbachia redistribute the endoplasmic reticulum to increase contact sites, and time lapse experiments reveal tight coupled dynamics suggesting important signalling events or nutrient uptake. They however do not affect the tubular or cisternal morphologies. A fraction of endoplasmic reticulum becomes clustered, allowing the endosymbionts to reside in between the endoplasmic reticulum and the Golgi apparatus, possibly modulating the traffic between these two organelles. Gene expression analyses and immunostaining studies suggest that Wolbachia achieve persistent infections at very high titers without triggering endoplasmic reticulum stress or enhanced ERAD-driven proteolysis, suggesting that amino acid salvage is achieved through modulation of other signalling pathways.Author summaryWolbachia are a genus of intracellular bacteria living in symbiosis with millions of arthropod species. They have the ability to block the transmission of arboviruses when introduced into mosquito vectors, by interfering with the cellular resources exploited by these viruses. Despite the biomedical interest of this symbiosis, little is known about the mechanisms by which Wolbachia survive and replicate in the host cell. We show here that the membrane composing the Wolbachia vacuole is acquired from the endoplasmic reticulum, a central organelle required for protein and lipid synthesis, and from which originates a vesicular trafficking toward the Golgi apparatus and the secretory pathway. Wolbachia modify the distribution of this organelle to increase their interactions with this source of membrane and likely of nutrients as well. In contrast to some intracellular pathogenic bacteria, the effect of Wolbachia on the cell homeostasis does not induce a stress on the endoplasmic reticulum. One of the consequences of such a stress would be an increased proteolysis used to relieve the cell from an excess of misfolded proteins. Incidentally, this shows that Wolbachia do not acquire amino acids from the host cell through this strategy.

scholarly journals Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1617 ◽  
Author(s):  
Jin Li ◽  
Deli Zhang ◽  
Bianca J. J. M. Brundel ◽  
Marit Wiersma
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Endoplasmic Reticulum ◽  
Cardiac Disease ◽  
Healthcare Costs ◽  
Central Component ◽  
Ageing Population ◽  
Mitochondrial Stress ◽  
Underlying Mechanisms

Cardiac disease is still the leading cause of morbidity and mortality worldwide, despite some exciting and innovative improvements in clinical management. In particular, atrial fibrillation (AF) and heart failure show a steep increase in incidence and healthcare costs due to the ageing population. Although research revealed novel insights in pathways driving cardiac disease, the exact underlying mechanisms have not been uncovered so far. Emerging evidence indicates that derailed proteostasis (i.e., the homeostasis of protein expression, function and clearance) is a central component driving cardiac disease. Within proteostasis derailment, key roles for endoplasmic reticulum (ER) and mitochondrial stress have been uncovered. Here, we describe the concept of ER and mitochondrial stress and the role of interactions between the ER and mitochondria, discuss how imbalance in the interactions fuels cardiac ageing and cardiac disease (including AF), and finally assess the potential of drugs directed at conserving the interaction as an innovative therapeutic target to improve cardiac function.

The role of microtubules in transport between the endoplasmic reticulum and Golgi apparatus in mammalian cells.

2005 ◽  
Vol 72 ◽  
pp. 1-13 ◽  
Author(s):  
Krysten J. Palmer ◽  
Peter Watson ◽  
David J. Stephens
Keyword(s):  
Endoplasmic Reticulum ◽  
Mammalian Cells ◽  
Secretory Pathway ◽  
Motor Proteins ◽  
Microtubule Cytoskeleton ◽  
Early Secretory Pathway ◽  
Golgi Transport ◽  
Intracellular Compartments ◽  
Retrograde Traffic

The organization of intracellular compartments and the transfer of components between them are central to the correct functioning of mammalian cells. Proteins and lipids are transferred between compartments by the formation, movement and subsequent specific fusion of transport intermediates. These vesicles and membrane clusters must be coupled to the cytoskeleton and to motor proteins that drive motility. Anterograde ER (endoplasmic reticulum)-to-Golgi transport, and the converse step of retrograde traffic from the Golgi to the ER, are now known to involve coupling of membranes to the microtubule cytoskeleton. Here we shall discuss our current understanding of the mechanisms that link membrane traffic in the early secretory pathway to the microtubule cytoskeleton in mammalian cells. Recent data have also provided molecular detail of functional co-ordination of motor proteins to specify directionality, as well as mechanisms for regulating motor activity by protein phosphorylation.

New insight on the role of liraglutide in alleviating dexamethasone-induced pancreatic cytotoxicity via improving redox status, autophagy flux and PI3K/Akt/Nrf2 signaling

2021 ◽  
Author(s):  
Walaa Elseady ◽  
Rasha Abd Ellatif ◽  
Remon Estfanous ◽  
Marwa Emam ◽  
Walaa Arafa Keshk
Keyword(s):  
Cell Function ◽  
Pancreatic Injury ◽  
Redox Status ◽  
Protective Role ◽  
Caspase 9 ◽  
Β Cell ◽  
Autophagy Flux ◽  
Β Cell Function ◽  
Underlying Mechanisms

Chronic glucocorticoids therapy is commonly complicated by steroid diabetes, while the underlying mechanisms are still elusive. Liraglutide a glucagon like peptide -1 was initially found to induce glycemic control and recently it was found to have many pleotropic effects. However, its role in pancreas remains unknown. So, the present study aims to estimate the protective role of liraglutide on dexamethasone-induced pancreatic cytotoxicity, and hyperglycemia with highlighting the possible biochemical, molecular and cellular underlying mechanisms. Twenty-eight male Wistar rats were involved in this study and were randomly divided into four groups. Group III & IV were treated with 1mg/kg dexamethasone daily for 10 days. Group II & IV were treated with liraglutide in a dose of 0.8 mg/kg/day for 2 weeks. Pancreatic caspase-9, Nrf2, pAkt and sequestrome1 (p62) levels were assessed by immunoassay. Moreover, phosphoinositide 3-kinase (PI3K) expression by real time PCR, LC3B expression by immunohistochemistry, glycemic status, β-cell function by HOMA-β index, and pancreatic redox status were assessed. Liraglutide improved blood glucose level, β-cell function, pancreatic caspase 9 level, redox status, and autophagy. Additionally, it increased pancreatic PI3K, pAkt and Nrf2 levels. Moreover, preservation of pancreatic histological and the ultrastructural morphological features of β- and α-cell were observed. In conclusion: Liraglutide protected against dexamethasone-induced pancreatic injury, hyperglycemia and decelerated the progression towards steroid diabetes via activating PI3K/Akt/Nrf2 signaling and autophagy flux pathways

scholarly journals Infection, Colonization, and Disease of Amaranthus hybridus Leaves by the Alternaria tenuissima Group

Plant Disease ◽  
2002 ◽  
Vol 86 (11) ◽  
pp. 1199-1205 ◽  
Author(s):  
J. T. Blodgett ◽  
W. J. Swart
Keyword(s):  
Host Cell ◽  
Cell Penetration ◽  
Amaranthus Hybridus ◽  
Wound Site ◽  
Alternaria Tenuissima ◽  
Host Cell Response ◽  
Leaf Surfaces ◽  
Chamber Studies ◽  
Growth Chamber Studies

With the increased use of Amaranthus hybridus as a leafy-vegetable crop in Africa and the recent identification of Alternaria leaf spot on this host in southern Africa, the role of this potentially damaging pathogen was investigated. The goals of this study were to test the pathogenicity of the Alternaria tenuissima group, determine how these fungi infect Amaranthus hybridus leaves, and examine the colonization pattern within host tissues. Asymptomatic leaves of Amaranthus hybridus were collected from two field sites in South Africa. Eight A. tenuissima group isolates collected from these leaves were used in inoculation experiments conducted in both greenhouse and growth chamber studies. Scanning electron microscopy revealed A. tenuissima-like conidia germinating on leaf surfaces and mycelia entering leaves only through stomata of both field-collected and artificially inoculated leaves. Unwounded, inoculated leaves had no symptoms, and light-microscopy observations of both asymptomatic field-collected and unwounded and inoculated leaves revealed hyphae in mesophyll tissue growing intercellularly with no host cell penetration or host-cell response. Seven of the eight isolates produced brown to black, circular to oval, necrotic lesions only at the wound site of injured and inoculated leaves. These results confirm that isolates of the A. tenuissima group can infect and colonize Amaranthus hybridus leaves in a manner consistent with other endophytic fungi, and suggest that these fungi can act as latent leaf pathogens when the host is altered by wounding.

scholarly journals Role of p97 and Syntaxin 5 in the Assembly of Transitional Endoplasmic Reticulum

2000 ◽  
Vol 11 (8) ◽  
pp. 2529-2542 ◽  
Author(s):  
Line Roy ◽  
John J.M. Bergeron ◽  
Christine Lavoie ◽  
Rob Hendriks ◽  
Jennifer Gushue ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Atp Hydrolysis ◽  
Smooth Endoplasmic Reticulum ◽  
Atp Depletion ◽  
Low Density ◽  
Transitional Endoplasmic Reticulum ◽  
Membrane Compartment ◽  
A Cell

Transitional endoplasmic reticulum (tER) consists of confluent rough and smooth endoplasmic reticulum (ER) domains. In a cell-free incubation system, low-density microsomes (1.17 g cc− 1) isolated from rat liver homogenates reconstitute tER by Mg2+GTP- and Mg2+ATP-hydrolysis–dependent membrane fusion. The ATPases associated with different cellular activities protein p97 has been identified as the relevant ATPase. The ATP depletion by hexokinase or treatment with either N-ethylmaleimide or anti-p97 prevented assembly of the smooth ER domain of tER. High-salt washing of low-density microsomes inhibited assembly of the smooth ER domain of tER, whereas the readdition of purified p97 with associated p47 promoted reconstitution. The t-SNARE syntaxin 5 was observed within the smooth ER domain of tER, and antisyntaxin 5 abrogated formation of this same membrane compartment. Thus, p97 and syntaxin 5 regulate assembly of the smooth ER domain of tER and hence one of the earliest membrane differentiated components of the secretory pathway.

scholarly journals AAA-ATPase p97/Cdc48p, a Cytosolic Chaperone Required for Endoplasmic Reticulum-Associated Protein Degradation

2002 ◽  
Vol 22 (2) ◽  
pp. 626-634 ◽  
Author(s):  
Efrat Rabinovich ◽  
Anat Kerem ◽  
Kai-Uwe Fröhlich ◽  
Noam Diamant ◽  
Shoshana Bar-Nun
Keyword(s):  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Binding Capacity ◽  
Immunoglobulin M ◽  
Aaa Atpase ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Yeast Mutants

ABSTRACT Endoplasmic reticulum-associated degradation (ERAD) disposes of aberrant proteins in the secretory pathway. Protein substrates of ERAD are dislocated via the Sec61p translocon from the endoplasmic reticulum to the cytosol, where they are ubiquitinated and degraded by the proteasome. Since the Sec61p channel is also responsible for import of nascent proteins, this bidirectional passage should be coordinated, probably by molecular chaperones. Here we implicate the cytosolic chaperone AAA-ATPase p97/Cdc48p in ERAD. We show the association of mammalian p97 and its yeast homologue Cdc48p in complexes with two respective ERAD substrates, secretory immunoglobulin M in B lymphocytes and 6myc-Hmg2p in yeast. The membrane 6myc-Hmg2p as well as soluble lumenal CPY*, two short-lived ERAD substrates, are markedly stabilized in conditional cdc48 yeast mutants. The involvement of Cdc48p in dislocation is underscored by the accumulation of ERAD substrates in the endoplasmic reticulum when Cdc48p fails to function, as monitored by activation of the unfolded protein response. We propose that the role of p97/Cdc48p in ERAD, provided by its potential unfoldase activity and multiubiquitin binding capacity, is to act at the cytosolic face of the endoplasmic reticulum and to chaperone dislocation of ERAD substrates and present them to the proteasome.

scholarly journals BPIFB6 Regulates Secretory Pathway Trafficking and Enterovirus Replication

2016 ◽  
Vol 90 (10) ◽  
pp. 5098-5107 ◽  
Author(s):  
Stefanie Morosky ◽  
Nicholas J. Lennemann ◽  
Carolyn B. Coyne
Keyword(s):  
Endoplasmic Reticulum ◽  
Host Cell ◽  
Golgi Complex ◽  
Secretory Pathway ◽  
Type I Diabetes ◽  
Enterovirus 71 ◽  
Type I ◽  
Virus Infections ◽  
Cell Functions ◽  
Coxsackievirus B

ABSTRACTBactericidal/permeability-increasing protein (BPI) fold-containing family B, member 3 (BPIFB3) is an endoplasmic reticulum (ER)-localized host factor that negatively regulates coxsackievirus B (CVB) replication through its control of the autophagic pathway. Here, we show that another member of the BPIFB family, BPIFB6, functions as a positive regulator of CVB, and other enterovirus, replication by controlling secretory pathway trafficking and Golgi complex morphology. We show that similar to BPIFB3, BPIFB6 localizes exclusively to the ER, where it associates with other members of the BPIFB family. However, in contrast to our findings that RNA interference (RNAi)-mediated silencing of BPIFB3 greatly enhances CVB replication, we show that silencing of BPIFB6 expression dramatically suppresses enterovirus replication in a pan-viral manner. Mechanistically, we show that loss of BPIFB6 expression induces pronounced alterations in retrograde and anterograde trafficking, which correlate with dramatic fragmentation of the Golgi complex. Taken together, these data implicate BPIFB6 as a key regulator of secretory pathway trafficking and viral replication and suggest that members of the BPIFB family participate in diverse host cell functions to regulate virus infections.IMPORTANCEEnterovirus infections are associated with a number of severe pathologies, such as aseptic meningitis, dilated cardiomyopathy, type I diabetes, paralysis, and even death. These viruses, which include coxsackievirus B (CVB), poliovirus (PV), and enterovirus 71 (EV71), co-opt the host cell secretory pathway, which controls the transport of proteins from the endoplasmic reticulum to the Golgi complex, to facilitate their replication. Here we report on the identification of a novel regulator of the secretory pathway, bactericidal/permeability-increasing protein (BPI) fold-containing family B, member 6 (BPIFB6), whose expression is required for enterovirus replication. We show that loss of BPIFB6 expression correlates with pronounced defects in the secretory pathway and greatly reduces the replication of CVB, PV, and EV71. Our results thus identify a novel host cell therapeutic target whose function could be targeted to alter enterovirus replication.

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