Cleavage and degradation of EDEM1 promotes coxsackievirus B3 replication via ATF6a‐mediated unfolded protein response signalling

Zhang, Huifang M.; Qiu, Ye; Zhao, Guangze; Wang, Hua; Chen, Yankuan T.; Aghakeshmiri, Sana; Hanson, P. J.; Yang, Decheng

doi:10.1111/cmi.13198

Cited by 3 publications

(3 citation statements)

References 52 publications

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“…ER stress is classified as activation of one or more ER stress signaling pathways, including IRE1α-XBP1, PERK (PKR-like endoplasmic reticulum kinase)-eIF2α and ATF6 pathways. 30–32 We failed to detect significant IRE1α-XBP1 activation in Myo-sEV MI/R treated adipocytes (data not shown). However, Myo-sEV MI/R significantly altered the expression of proteins involved in 2 other ER stress pathways (Figure 2B).…”

Section: Resultsmentioning

confidence: 91%

“…ER stress is identified by activation of 3 ER stress signaling pathways, including IRE1α-XBP1 pathway, PERK-eIF2α pathway, and ATF6 pathway. 30–32 We failed to detect significant IRE1α-XBP1 activation in eWAT after MI/R and adipocytes after Myo-sEV MI/R treatment. However, 2 other ER stress pathways are significantly activated by Myo-sEV MI/R .…”

Section: Discussionmentioning

confidence: 92%

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Ischemic Heart-Derived Small Extracellular Vesicles Impair Adipocyte Function

Gan

Liu

Xie

et al. 2022

Circulation Research

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Background: Acute myocardial infarction (AMI) patients suffer systemic metabolic dysfunction via incompletely understood mechanisms. Adipocytes play critical role in metabolic homeostasis. The impact of AMI upon adipocyte function is unclear. Small extracellular vesicles (sEV) critically contribute to organ-organ communication. Whether and how sEV mediate post-MI cardiomyocyte/adipocyte communication remain unknown. Methods Plasma sEV were isolated from sham control (Pla-sEV Sham ) or 3 hours after myocardial ischemia/reperfusion (Pla-sEV MI/R ) and incubated with adipocytes for 24 hours. Compared to Pla-sEV Sham , Pla-sEV MI/R significantly altered expression of genes known to be important in adipocyte function, including a well-known metabolic regulatory/cardioprotective adipokine, adiponectin (APN). Pla-sEV MI/R activated two (PERK-CHOP and ATF6-EDEM pathways) of the three endoplasmic reticulum (ER) stress pathways in adipocytes. These pathological alterations were also observed in adipocytes treated with sEVs isolated from adult cardiomyocytes subjected to in vivo MI/R (Myo-sEV MI/R ). Bioinformatic/RT-qPCR analysis demonstrates that the members of miR-23-27-24 cluster are significantly increased in Pla-sEV MI/R , Myo-sEV MI/R , and adipose tissue of MI/R animals. Administration of cardiomyocyte-specific miR-23-27-24 sponges abolished adipocyte miR-23-27-24 elevation in MI/R animals, supporting the cardiomyocyte origin of adipocyte miR-23-27-24 cluster. In similar fashion to Myo-sEV MI/R , a miR-27a mimic activated PERK-CHOP and ATF6-EDEM mediated ER stress. Conversely, a miR-27a inhibitor significantly attenuated Myo-sEV MI/R -induced ER stress and restored APN production. Results: An unbiased approach identified EDEM3 as a novel downstream target of miR-27a. Adipocyte EDEM3 deficiency phenocopied multiple pathological alterations caused by Myo-sEV MI/R , whereas EDEM3 overexpression attenuated Myo-sEV MI/R -resulted ER stress. Finally, administration of GW4869 or cardiomyocyte-specific miR-23-27-24 cluster sponges attenuated adipocyte ER stress, improved adipocyte endocrine function, and restored plasma APN levels in MI/R animals. Conclusion: We demonstrate for the first time that MI/R causes significant adipocyte ER stress and endocrine dysfunction by releasing miR-23-27-24 cluster-enriched sEV. Targeting sEV-mediated cardiomyocyte-adipocyte pathologic communication may be of therapeutic potential to prevent metabolic dysfunction after MI/R.

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 92%

Ischemic Heart-Derived Small Extracellular Vesicles Impair Adipocyte Function

Gan

Liu

Xie

et al. 2022

Circulation Research

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“…Cellular proteins were then collected at 12 and 24 h pi to determine the effect of inhibition on γ-catenin level by Western blot analysis. All these inhibitors were used at a lower concentration that could not significantly affect CVB3 replication based on our previous experience (Yuan et al, 2005b;Qiu et al, 2017;Zhang et al, 2020).…”

Section: Cell Treatment With Inhibitor Against Proteasome Gsk3 or Cmentioning

confidence: 99%

Cleavage of Desmosomal Cadherins Promotes γ-Catenin Degradation and Benefits Wnt Signaling in Coxsackievirus B3-Induced Destruction of Cardiomyocytes

et al. 2020

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Coxsackievirus B3 (CVB3) is the primary etiologic agent of viral myocarditis, a major heart disease that occurs predominantly in children and young adolescents. In the heart, intercalated disks (ICD) are important structural formations that connect adjacent cardiomyocytes to maintain cardiac architecture and mediate signal communication. Deficiency in ICD components, such as desmosome proteins, leads to heart dysfunction. γ-catenin, a component protein of desmosomes, normally binds directly to desmocollin-2 and desmoglein-2. In this study, we found that CVB3 infection downregulated γ-catenin at the protein level but not the mRNA level in mouse HL-1 cardiomyocytes. We further found that this reduction of γ-catenin protein is a result of ubiquitin proteasome-mediated degradation, since the addition of proteasome inhibitor MG132 inhibited γ-catenin downregulation. In addition, we found that desmocollin-2 and desmoglein-2 were cleaved by both viral protease 3C and virus-activated cellular caspase, respectively. These cleavages led to the release of bound γ-catenin from the desmosome into the cytosol, resulting in rapid degradation of γ-catenin. Since γ-catenin shares high sequence homology with β-catenin in binding the TCF/LEF transcription factor, we further studied the effect of γ-catenin degradation on Wnt/β-catenin signaling. Luciferase assay showed that γ-catenin expression inhibited Wnt/β-catenin signaling. This finding was substantiated by qPCR to show that overexpression of γ-catenin downregulated transcription of Wnt signal target genes, c-myc and MMP9, while silencing γ-catenin upregulated these target genes. Finally, we demonstrated that γcatenin expression inhibited CVB3 replication. In search for the underlying mechanism, we found that silencing γ-catenin caused down-regulation of interferon-β and its stimulated antiviral genes MDA5, MAVS, and ISG15. Taken together, our results indicate, for the first time, that CVB3 infection causes cardiomyocyte death through, at least in

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Genetic disruption of mammalian endoplasmic reticulum‐associated protein degradation: Human phenotypes and animal and cellular disease models

Badawi

Mohamed

Varghese

et al. 2023

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Endoplasmic reticulum-associated protein degradation (ERAD) is a stringent quality control mechanism through which misfolded, unassembled and some native proteins are targeted for degradation to maintain appropriate cellular and organelle homeostasis. Several in vitro and in vivo ERAD-related studies have provided mechanistic insights into ERAD pathway activation and its consequent events; however, a majority of these have investigated the effect of ERAD substrates and their consequent diseases affecting the degradation process. In this review, we present all reported human single-gene disorders caused by genetic variation in genes that encode ERAD components rather than their substrates. Additionally, after extensive literature survey, we present various genetically manipulated higher cellular and mammalian animal models that lack specific components involved in various stages of the ERAD pathway.

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Cleavage and degradation of EDEM1 promotes coxsackievirus B3 replication via ATF6a‐mediated unfolded protein response signalling

Cited by 3 publications

References 52 publications

Ischemic Heart-Derived Small Extracellular Vesicles Impair Adipocyte Function

Ischemic Heart-Derived Small Extracellular Vesicles Impair Adipocyte Function

Cleavage of Desmosomal Cadherins Promotes γ-Catenin Degradation and Benefits Wnt Signaling in Coxsackievirus B3-Induced Destruction of Cardiomyocytes

Genetic disruption of mammalian endoplasmic reticulum‐associated protein degradation: Human phenotypes and animal and cellular disease models

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