Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD

Patel, Chaitanya; Saad, Haddas; Shenkman, Marina; Lederkremer, Gerardo Z.

doi:10.3390/cells9092138

Cited by 19 publications

(18 citation statements)

References 118 publications

(141 reference statements)

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“…The calnexin (CNX)/calreticulin (CRT) cycle, composed of lectin-like molecular chaperones CNX and CRT, is an essential part of the ERQC system that depends on modifying protein glycosylation and sugar chain structures in the ER ( 10 ). The CNX/CRT cycle is one of the important monitoring mechanisms for protein folding and assembly ( 11 ). The disulfide bond isomerase ER protein 57 (ERP57), involved in the CNX/CRT cycle, catalyzes the oxidation and isomerization of disulfide bonds in glycoproteins and binds to CNX/CRT glycoproteins ( 12 , 13 ).…”

Section: Introductionmentioning

confidence: 99%

Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG‑A561V protein

Huang

Zheng

et al. 2021

Int J Mol Med

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Long QT syndrome type 2 is caused by a mutation in the human-ether-a-go-go-related gene (HERG) gene encoding the rapidly activating delayed rectifier K-current. HERG is a key cell membrane glycoprotein; however, whether the maturation process of HERG protein involves key molecules derived from the calnexin (cNX)/calreticulin (cRT) cycle and how these molecules work remains unknown. Using western blotting, the present study screened the key molecules CNX/CRT/endoplasmic reticulum protein 57 (ERP57) involved in this cycle, and it was revealed that the protein expression levels of cNX/cRT/ERP57 in wild-type (WT)/A561V cells were increased compared with those in WT cells (n=3; P<0.05). Additionally, a co-immunoprecipitation experiment was used to reveal that the ability of cNX/ERP57/cRT to interact with HERG was significantly increased in A561V and WT/A561V cells (n=3; P<0.05). A plasmid lacking the bb' domain of ERP57 was constructed and it was demonstrated that the key site of ERP57 binding to CRT and immature HERG protein is the bb' domain. The whole-cell patch-clamp technique detected that the tail current density increased by 46% following overexpression of cRT and by 53% following overexpression of ERP57 in WT/A561V cells. Overexpression of CRT and ERP57 could increased HERG protein levels on the membrane detected by confocal imaging. Furthermore, overexpression of ERP57 and cRT proteins could restore the HERG-A561V mutant protein trafficking process and rescue the dominant-negative suppression of WT. Overall, ERP57/CRT served a crucial role in the HERG-A561V mutant protein trafficking deficiency and degradation process.

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Section: Introductionmentioning

confidence: 99%

Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG‑A561V protein

Huang

Zheng

et al. 2021

Int J Mol Med

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“…Ageing is related to changes in the renewal of proteins and mitochondria, and the aggregation of misfolded proteins seems to be a central feature in ageing and in age-related diseases, such as Alzheimer's disease and type 2 diabetes [31,32]. Several selenoproteins, i.a., selenoproteins F, K, S and T, which reside in the endoplasmic reticulum (ER), appear to participate in the control and removal of misfolded proteins and in the protection against ER stress, also including control of calcium homeostasis [4,5,33]. Hence, adequate selenium status may play a role in healthy ageing by these mechanisms also.…”

Section: Selenium Nutrition: From Basic To Clinical Aspectsmentioning

confidence: 99%

“…The trace element selenium (Se), as a significant essential nutritional factor, may remodel biochemical and physiological changes accompanying ageing by improving immune functions, mediating metabolic homeostasis and antioxidant defense, and also in the removal of misfolded proteins [4][5][6]. Se deficiency in ageing populations seems to increase Biomolecules 2021, 11, 1478 2 of 14 the risk of developing age-related diseases [7,8].…”

Section: Introductionmentioning

confidence: 99%

Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing. A Review

et al. 2021

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Selenium (Se) is an essential dietary trace element that plays an important role in the prevention of inflammation, cardiovascular diseases, infections, and cancer. Selenoproteins contain selenocysteine in the active center and include, i.e., the enzymes thioredoxin reductases (TXNRD1–3), glutathione peroxidases (GPX1–4 and GPX6) and methionine sulfoxide reductase, involved in immune functions, metabolic homeostasis, and antioxidant defense. Ageing is an inevitable process, which, i.e., involves an imbalance between antioxidative defense and reactive oxygen species (ROS), changes in protein and mitochondrial renewal, telomere attrition, cellular senescence, epigenetic alterations, and stem cell exhaustion. These conditions are associated with mild to moderate inflammation, which always accompanies the process of ageing and age-related diseases. In older individuals, Se, by being a component in protective enzymes, operates by decreasing ROS-mediated inflammation, removing misfolded proteins, decreasing DNA damage, and promoting telomere length. Se-dependent GPX1–4 and TXNRD1–3 directly suppress oxidative stress. Selenoprotein H in the cell nucleus protects DNA, and selenoproteins residing in the endoplasmic reticulum (ER) assist in the removal of misfolded proteins and protection against ER stress. In this review, we highlight the role of adequate Se status for human ageing and prevention of age-related diseases, and further its proposed role in preservation of telomere length in middle-aged and elderly individuals.

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“…The addition of a C terminal cysteine residue to the B subunit has facilitated the generation of such conjugates via disulfide linkage [138]. Such linker conjugates will be cleaved by reduction in the tumour ER [135,139,140] to allow specific ER cargo delivery [141]. A peptide which promotes ER retrotranslocon transit can be coupled to increase cytosolic cargo access [142,143].…”

Section: B Subunit Conjugatesmentioning

confidence: 99%

Therapeutic Uses of Bacterial Subunit Toxins

Lingwood

2021

Toxins

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The B subunit pentamer verotoxin (VT aka Shiga toxin-Stx) binding to its cellular glycosphingolipid (GSL) receptor, globotriaosyl ceramide (Gb3) mediates internalization and the subsequent receptor mediated retrograde intracellular traffic of the AB5 subunit holotoxin to the endoplasmic reticulum. Subunit separation and cytosolic A subunit transit via the ER retrotranslocon as a misfolded protein mimic, then inhibits protein synthesis to kill cells, which can cause hemolytic uremic syndrome clinically. This represents one of the most studied systems of prokaryotic hijacking of eukaryotic biology. Similarly, the interaction of cholera AB5 toxin with its GSL receptor, GM1 ganglioside, is the key component of the gastrointestinal pathogenesis of cholera and follows the same retrograde transport pathway for A subunit cytosol access. Although both VT and CT are the cause of major pathology worldwide, the toxin–receptor interaction is itself being manipulated to generate new approaches to control, rather than cause, disease. This arena comprises two areas: anti neoplasia, and protein misfolding diseases. CT/CTB subunit immunomodulatory function and anti-cancer toxin immunoconjugates will not be considered here. In the verotoxin case, it is clear that Gb3 (and VT targeting) is upregulated in many human cancers and that there is a relationship between GSL expression and cancer drug resistance. While both verotoxin and cholera toxin similarly hijack the intracellular ERAD quality control system of nascent protein folding, the more widespread cell expression of GM1 makes cholera the toxin of choice as the means to more widely utilise ERAD targeting to ameliorate genetic diseases of protein misfolding. Gb3 is primarily expressed in human renal tissue. Glomerular endothelial cells are the primary VT target but Gb3 is expressed in other endothelial beds, notably brain endothelial cells which can mediate the encephalopathy primarily associated with VT2-producing E. coli infection. The Gb3 levels can be regulated by cytokines released during EHEC infection, which complicate pathogenesis. Significantly Gb3 is upregulated in the neovasculature of many tumours, irrespective of tumour Gb3 status. Gb3 is markedly increased in pancreatic, ovarian, breast, testicular, renal, astrocytic, gastric, colorectal, cervical, sarcoma and meningeal cancer relative to the normal tissue. VT has been shown to be effective in mouse xenograft models of renal, astrocytoma, ovarian, colorectal, meningioma, and breast cancer. These studies are herein reviewed. Both CT and VT (and several other bacterial toxins) access the cell cytosol via cell surface ->ER transport. Once in the ER they interface with the protein folding homeostatic quality control pathway of the cell -ERAD, (ER associated degradation), which ensures that only correctly folded nascent proteins are allowed to progress to their cellular destinations. Misfolded proteins are translocated through the ER membrane and degraded by cytosolic proteosome. VT and CT A subunits have a C terminal misfolded protein mimic sequence to hijack this transporter to enter the cytosol. This interface between exogenous toxin and genetically encoded endogenous mutant misfolded proteins, provides a new therapeutic basis for the treatment of such genetic diseases, e.g., Cystic fibrosis, Gaucher disease, Krabbe disease, Fabry disease, Tay-Sachs disease and many more. Studies showing the efficacy of this approach in animal models of such diseases are presented.

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Oxidoreductases in Glycoprotein Glycosylation, Folding, and ERAD

Cited by 19 publications

References 118 publications

Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG‑A561V protein

Role and mechanism of chaperones calreticulin and ERP57 in restoring trafficking to mutant HERG‑A561V protein

Impact of Selenium on Biomarkers and Clinical Aspects Related to Ageing. A Review

Therapeutic Uses of Bacterial Subunit Toxins

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