CAR: A key regulator of adhesion and inflammation

Ortiz-Zapater, Elena; Santis, George; Parsons, Maddy

doi:10.1016/j.biocel.2017.05.025

Cited by 39 publications

(35 citation statements)

References 28 publications

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“…In this study, the proximal D2 domain of CAR was identified as the active binding domain, based on data showing that direct binding of FAdV-4 to purified D2-CAR significantly decreased viral infectivity in susceptible LMH cells. Although different CAR homologs showed 56.8-64.0% aa identity, different CAR proteins had similar structures and location in host cells [39,40], which might explain its utility by various types of AdVs in infecting different hosts. Nevertheless, the distal D1 domain of CAR is usually reported to directly mediate homophilic interactions responsible for high-affinity binding to AdV fibre proteins [36,38,41].…”

Section: Discussionmentioning

confidence: 99%

Identification of chicken CAR homology as a cellular receptor for the emerging highly pathogenic fowl adenovirus 4 via unique binding mechanism

Pan

Wang

Gao

et al. 2020

Emerging Microbes & Infections

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Since 2015, the prevalence of severe hepatitis-hydropericardium syndrome, which is caused by the novel genotype fowl adenovirus serotype 4 (FAdV-4), has increased in China and led to considerable economic losses. The replication cycle of FAdV-4, especially the emerging highly pathogenic novel genotype FAdV-4, remains largely unknown. The adenovirus fibre interacts with the cellular receptor as the initial step in adenovirus (AdV) infection. In our previous studies, the complete genome sequence showed that the fibre patterns of FAdV-4 were distinct from all other AdVs. Here, proteinblockage and antibody-neutralization assays were performed to confirm that the novel FAdV-4 short fibre was critical for binding to susceptible leghorn male hepatocellular (LMH) cells. Subsequently, fibre 1 was used as bait to investigate the receptor on LMH cells via mass spectrometry. The chicken coxsackie and adenovirus receptor (CAR) protein was confirmed as the novel FAdV-4 receptor in competition assays. We further identified the D2 domain of CAR (D2-CAR) as the active domain responsible for binding to the short fibre of the novel FAdV-4. Taken together, these findings demonstrate for the first time that the chicken CAR homolog is a cellular receptor for the novel FAdV-4, which facilitates viral entry by interacting with the viral short fibre through the D2 domain. Collectively, these findings provide an in-depth understanding of the mechanisms of the emerging novel genotype FAdV-4 invasion and pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Identification of chicken CAR homology as a cellular receptor for the emerging highly pathogenic fowl adenovirus 4 via unique binding mechanism

Pan

Wang

Gao

et al. 2020

Emerging Microbes & Infections

View full text Add to dashboard Cite

show abstract

“…CAR belongs to the CTX subfamily of the immunoglobulin superfamily, and it is originally known to be the primary attachment protein for viruses to enter the cells [ 16 ]. Although the cellular function of CAR is largely unknown, recent studies suggested that CAR mediates cell-cell adhesion through its association with epithelial TJs [ 17 ], suggesting the potential role of CAR in regulating permeability of gut barriers—an important indicator of IBD pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Protective Role of Coxsackie-Adenovirus Receptor in the Pathogenesis of Inflammatory Bowel Diseases

Chen

Liu

et al. 2018

BioMed Research International

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Aim To investigate the role of Coxsackie-adenovirus receptor (CAR) in inflammatory bowel disease (IBD). Background CAR, a type I transmembrane protein with functions in virus attachment, has been shown to be associated with epithelial tight junctions (TJs) and mediates cell adhesion, implying its potential roles in the pathogenesis of IBD. Methods and Materials To determine the effect of CAR in IBD using QPCR and Western blotting to determine the expression of CAD in TNF-α induced NCM460 and SW480 cells and IBD tissues compared to control groups. Furthermore, TJs dysregulation, FITC-Dextran permeability assay, qRT-PCR, Western blot, and IF assessed the permeability in CAR overexpressed cells treated with TNF-α. HE, qRT-PCR, Western blot, and IHC assay were used to assess the CAR overexpressed cells whether they have the effect to cure DSS induced ulcerative colitis rat model in vivo. Result We found CAR levels in human colon cell lines are significantly downregulated under the treatment of tumor necrosis factor-alpha (TNF-α). Furthermore, overexpression of CAR markedly prevented TNF-α induced inflammatory response, TJs dysregulation, and permeability disruption (FITC-Dextran permeability assay) in cells. Consistent with these findings in vitro, we found that CAR overexpression could suppress gut inflammation, attenuate the downregulation of TJ protein ZO-1 and Occludin, and limit the induction of barrier permeability in a DSS induced ulcerative colitis rat model in vivo. Together, our findings strongly suggest that CAR could protect tight junctions and has an anti-inflammatory effect during the pathogenesis of IBD. Thus CAR may serve as a therapeutic target for the diagnosis and treatment of IBD.

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“…IFRD1 encodes a protein related to interferon gamma and represses transcriptional activity of NF‐kB, contributing to explain the DUX4 immunosuppressive action . On the other hand, DUX4 upregulates CXADR and CXCR4, which are receptors involved in the migration of leukocytes from the blood into inflamed tissues . Among the innate immunity pathways, several membrane attack complex‐related genes were also found highly expressed in normal appearing FSHD muscle fibers .…”

Section: Consequence Of Epigenetic Derepression: the Dux4 Immune Derementioning

confidence: 99%

Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy

et al. 2020

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Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is caused either by the contraction of the D4Z4 macrosatellite repeat at the distal end of chromosome 4q to a size of 1 to 10 repeat units (FSHD1) or by mutations in D4Z4 chromatin modifiers such as Structural Maintenance of Chromosomes Hinge Domain Containing 1 (FSHD2). These two genotypes share a phenotype characterized by progressive and often asymmetric muscle weakening and atrophy, and common epigenetic alterations of the D4Z4 repeat. All together, these epigenetic changes converge the two genetic forms into one disease and explain the derepression of the DUX4 gene, which is otherwise kept epigenetically silent in skeletal muscle. DUX4 is consistently transcriptionally upregulated in FSHD1 and FSHD2 skeletal muscle cells where it is believed to exercise a toxic effect. Here we provide a review of the recent literature describing the progress in understanding the complex genetic and epigenetic architecture of FSHD, with a focus on one of the consequences that these epigenetic changes inflict, the DUX4-induced immune deregulation cascade. Moreover, we review the latest therapeutic strategies, with particular attention to the potential of epigenetic correction of the FSHD locus. K E Y W O R D S

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CAR: A key regulator of adhesion and inflammation

Cited by 39 publications

References 28 publications

Identification of chicken CAR homology as a cellular receptor for the emerging highly pathogenic fowl adenovirus 4 via unique binding mechanism

Identification of chicken CAR homology as a cellular receptor for the emerging highly pathogenic fowl adenovirus 4 via unique binding mechanism

Protective Role of Coxsackie-Adenovirus Receptor in the Pathogenesis of Inflammatory Bowel Diseases

Consequences of epigenetic derepression in facioscapulohumeral muscular dystrophy

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