New insights into the role of endoplasmic reticulum‐associated degradation in Bartter Syndrome Type 1

2021 ◽  
Author(s):  
Irfan Shaukat ◽  
Dalal Bakhos‐Douaihy ◽  
Yingying Zhu ◽  
Elie Seaayfan ◽  
Sylvie Demaretz ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Bartter Syndrome ◽  
Syndrome Type ◽  
Endoplasmic Reticulum Associated Degradation

scholarly journals EDEM2 stably disulfide-bonded to TXNDC11 catalyzes the first mannose trimming step in mammalian glycoprotein ERAD

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ginto George ◽  
Satoshi Ninagawa ◽  
Hirokazu Yagi ◽  
Taiki Saito ◽  
Tokiro Ishikawa ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Gene Knockout ◽  
Covalent Bonding ◽  
Cxxc Motif ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Endoplasmic Reticulum Protein ◽  
Hct116 Cells

Sequential mannose trimming of N-glycan (Man9GlcNAc2 -> Man8GlcNAc2 -> Man7GlcNAc2) facilitates endoplasmic reticulum-associated degradation of misfolded glycoproteins (gpERAD). Our gene knockout experiments in human HCT116 cells have revealed that EDEM2 is required for the first step. However, it was previously shown that purified EDEM2 exhibited no α1,2-mannosidase activity toward Man9GlcNAc2 in vitro. Here, we found that EDEM2 was stably disulfide-bonded to TXNDC11, an endoplasmic reticulum protein containing five thioredoxin (Trx)-like domains. C558 present outside of the mannosidase homology domain of EDEM2 was linked to C692 in Trx5, which solely contains the CXXC motif in TXNDC11. This covalent bonding was essential for mannose trimming and subsequent gpERAD in HCT116 cells. Furthermore, EDEM2-TXNDC11 complex purified from transfected HCT116 cells converted Man9GlcNAc2 to Man8GlcNAc2(isomerB) in vitro. Our results establish the role of EDEM2 as an initiator of gpERAD, and represent the first clear demonstration of in vitro mannosidase activity of EDEM family proteins.

scholarly journals Plasma Lipopolysaccharide Concentrations in Cardiorenal Syndrome Type 1

2019 ◽  
Vol 9 (5) ◽  
pp. 308-315
Author(s):  
Grazia Maria Virzì ◽  
Andrea Breglia ◽  
Ghada Ankawi ◽  
Chiara Bolin ◽  
Massimo de Cal ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Cardiorenal Syndrome ◽  
Syndrome Type ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Significant Difference ◽  
Renal Markers ◽  
Neutrophil Gelatinase ◽  
Time Of Admission

Background: Cardiorenal syndrome (CRS) type 1 is characterized by a rapid worsening of cardiac function that leads to acute kidney injury (AKI). This study evaluated the role of lipopolysaccharide (LPS) in the development of AKI in patients with acute heart failure (AHF) and its relationship with renal parameters, to enable a better comprehension of the pathophysiology of CRS type 1. Methods: We enrolled 32 AHF patients, 15 of whom were classified as having CRS type 1. Eight of these 15 exhibited AKI at the time of admission (caused by AHF) and the other 7 developed AKI during their stay in hospital (in the first 48 h). We evaluated the plasmatic LPS concentrations as well as conventional (serum creatinine [sCr] and urea) and unconventional (neutrophil gelatinase-associated lipocalin [NGAL] and cystatin C) renal markers. Results: LPS levels were significantly higher in the CRS type 1 patients. No significant difference in LPS level was found in patients who were admitted with AKI and those developed AKI in hospital, but there was a tendency towards a higher level of LPS in CRS type 1 patients admitted with AKI. The LPS concentrations at admission were similar in CRS type 1 survivors (n = 12) and nonsurvivors (n = 3) (p = 0.22). We observed a positive correlation between LPS level and NGAL, Scr at admission and peak Scr during hospitalization and urea at admission. Conclusion: CRS type 1 patients present with an increased level of LPS and there is a direct correlation between LPS and renal parameters. This pilot research is the first study to explore the premise of LPS as novel pathophysiological factor in CRS type 1.

scholarly journals Role of peripheral endothelin receptors in an animal model of complex regional pain syndrome type 1 (CRPS-I)

Pain ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 174-183 ◽  
Author(s):  
Magali Millecamps ◽  
Andre Laferrière ◽  
Vaigunda J. Ragavendran ◽  
Laura S. Stone ◽  
Terence J. Coderre
Keyword(s):  
Animal Model ◽  
Complex Regional Pain Syndrome ◽  
Pain Syndrome ◽  
Endothelin Receptors ◽  
Syndrome Type

scholarly journals Ghrelin’s Effects on Proinflammatory Cytokine Mediated Apoptosis and Their Impact onβ-Cell Functionality

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Antonia Diaz-Ganete ◽  
Gloria Baena-Nieto ◽  
Isabel M. Lomas-Romero ◽  
Jose Francisco Lopez-Acosta ◽  
Irene Cozar-Castellano ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Endoplasmic Reticulum Stress ◽  
Cell Mass ◽  
Slowing Down ◽  
Stress Markers ◽  
Murine Cell Line ◽  
Survival Pathways

Ghrelin is a peptidic hormone, which stimulates cell proliferation and inhibits apoptosis in several tissues, including pancreas. In preclinical stage of type 1 diabetes, proinflammatory cytokines generate a destructive environment forβ-cells known as insulitis, which results in loss ofβ-cell mass and impaired insulin secretion, leading to diabetes. Our aim was to demonstrate that ghrelin could preserveβ-cell viability, turnover rate, and insulin secretion acting as a counter balance of cytokines. In the present work we reproduced proinflammatory milieu found in insulitis stage by treating murine cell line INS-1E and rat islets with a cytokine cocktail including IL-1β, IFNγ, and TNFαand/or ghrelin. Several proteins involved in survival pathways (ERK 1/2 and Akt/PKB) and apoptosis (caspases and Bcl-2 protein family and endoplasmic reticulum stress markers) as well as insulin secretion were analyzed. Our results show that ghrelin alone has no remarkable effects onβ-cells in basal conditions, but interestingly it activates cell survival pathways, downregulates apoptotic mediators and endoplasmic reticulum stress, and restores insulin secretion in response to glucose when beta-cells are cytokine-exposed. These data suggest a potential role of ghrelin in preventing or slowing down the transition from a preclinical to clinically established diabetes by ameliorating the effects of insulitis onβ-cells.

scholarly journals The Role of Cell-Free Plasma DNA in Patients with Cardiorenal Syndrome Type 1

2021 ◽  
pp. 1-8
Author(s):  
Grazia Maria Virzì ◽  
Anna Clementi ◽  
Sabrina Milan Manani ◽  
Chiara Castellani ◽  
Giovanni Giorgio Battaglia ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Kidney Injury ◽  
Cardiorenal Syndrome ◽  
Syndrome Type ◽  
Plasma Dna ◽  
Apoptosis And Inflammation ◽  
Factor Α ◽  
Clinical Conditions

<b><i>Background:</i></b> Recent research highlighted the potential role of circulating cell-free DNA (cfDNA), resulted by apoptosis or cell necrosis, as a prognostic marker in the setting of different clinical conditions. Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Apoptosis of renal epithelial cells is proposed as a mechanism involved in CRS type 1. In this study, we investigated cfDNA levels in patients with acute heart failure (AHF) and CRS type 1 and the possible correlation between cfDNA levels and inflammatory and apoptotic parameters. <b><i>Methods:</i></b> We enrolled 17 AHF patients and 15 CRS type 1 who exhibited AKI at the time of admission (caused by AHF) or developed AKI during the first 48 h from admission. cfDNA was extracted from plasma and quantified by real-time polymerase chain reaction. Plasma levels of NGAL, tumor necrosis factor-α, interleukin (IL)-6, IL-18, and caspase-3 were measured. <b><i>Results:</i></b> We observed significantly higher levels of cfDNA in patients with CRS type 1 than patients with AHF. Caspase-3, IL-6, IL-18, and NGAL levels resulted significantly increased in patients with CRS type 1. Moreover, a positive correlation between cfDNA levels and caspase-3 levels was found, as well as between cfDNA levels and IL-6 and renal parameters. <b><i>Conclusion:</i></b> Our study explores the premise of cfDNA as a marker for apoptosis and inflammation in CRS type 1 patients. cfDNA could potentially serve as an index for noninvasive monitoring of tissue damage and apoptosis in patients with AKI induced by AHF.

scholarly journals PACS-2 attenuates diabetic kidney disease via the enhancement of mitochondria-associated endoplasmic reticulum membrane formation

2021 ◽  
Vol 12 (12) ◽  
Author(s):  
Mei Xue ◽  
Ting Fang ◽  
Hongxi Sun ◽  
Ying Cheng ◽  
Ting Li ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Diabetic Kidney Disease ◽  
Pathological Process ◽  
Endoplasmic Reticulum Membrane ◽  
Protective Effects ◽  
Diabetic Kidney ◽  
Renal Tubular

AbstractThe altered homeostasis of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) was closely associated with the pathological process of nervous system diseases and insulin resistance. Here, the exact implication of phosphofurin acidic cluster sorting protein 2 (PCAS-2), an anchor protein in the MAM interface, in diabetic kidney disease was investigated. In the kidneys of type 1 and type 2 diabetes mice and HG-induced HK-2 cells, a notable disruption of ER-mitochondria interactions, accompanied by a decreased PACS-2 expression in all subcellular fractions. Furthermore, PACS-2 knockout mice with diabetes displayed accelerated development of proteinuria, deterioration of kidney function, and aggravated disruption of MAM area, ER stress, mitochondrial dysfunction, renal apoptosis, and fibrosis. However, overexpression of PACS-2 effectively protected diabetic kidneys and HG-treated HK-2 cells from renal tubular impairments. Importantly, experimental uncoupling of ER-mitochondria contacts reversed the protective effects of PACS-2 restoration on HK-2 cells under HG conditions. In summary, our data indicate a pivotal role of PACS-2 in the development of diabetic renal tubular injury via the stabilization of MAM.

scholarly journals Efect of Sec61 interaction with Mpd1 on Endoplasmic Reticulum- Associated Degradation

2018 ◽  
Author(s):  
Fábio Pereira ◽  
Mandy Rettel ◽  
Frank Stein ◽  
Mikhail M. Savitski ◽  
Ian Collinson ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Import ◽  
Retrograde Transport ◽  
Secretory Proteins ◽  
Chemical Crosslinking ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Channel Opening ◽  
Interaction Partners ◽  
Sec61 Channel

AbstractProteins that misfold in the endoplasmic reticulum (ER) are transported back to the cytosol for ER-associated degradation (ERAD). The Sec61 channel is one of the candidates for the retrograde transport conduit. Channel opening from the ER lumen must be triggered by ERAD factors and substrates. Here we identified new lumenal interaction partners of Sec61 by chemical crosslinking and mass spectrometry. In addition to known Sec61 interactors we detected ERAD factors including Cue1, Ubc6, Ubc7, Asi3, and Mpd1. We show that the CPY* ERAD factor Mpd1 binds to the lumenal Sec61 hinge region. Deletion of the Mpd1 binding site reduced the interaction between both proteins and caused an ERAD defect specific for CPY* without affecting protein import into the ER or ERAD of other substrates. Our data suggest that Mpd1 binding to Sec61 is a prerequisite for CPY* ERAD and confirm a role of Sec61 in ERAD of misfolded secretory proteins.

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