Isoform-Specific Regulation and Localization of the Coxsackie and Adenovirus Receptor in Human Airway Epithelia

Excoffon, Katherine J. D. A.; Gansemer, Nicholas D.; Mobily, Matthew; Karp, Philip H.; Parekh, Kalpaj R.; Zabner, Joseph

doi:10.1371/journal.pone.0009909

Cited by 61 publications

(108 citation statements)

References 44 publications

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“…In addition to two isoforms (CXADR7 and CXADR8) that are known to be localised at the membrane, there are three more (CXADR4/7, CXADR3/7 and CXADR2/7) that do not contain a transmembrane domain and are meant to be accumulated in the cytoplasm or to be secreted (Tomko et al 1997, Thoelen et al 2001, Dö rner et al 2004, Excoffon et al 2010. We showed that expanded blastocysts express transmembrane CXADR and CXADR3/7, which correspond with membrane CAR and intracellular CAR protein, respectively.…”

Section: Discussionmentioning

confidence: 99%

CAR expression in human embryos and hESC illustrates its role in pluripotency and tight junctions

Krivega¹,

Geens²,

Velde³

2014

Reproduction

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Coxsackie virus and adenovirus receptor, CXADR (CAR), is present during embryogenesis and is involved in tissue regeneration, cancer and intercellular adhesion. We investigated the expression of CAR in human preimplantation embryos and embryonic stem cells (hESC) to identify its role in early embryogenesis and differentiation. CAR protein was ubiquitously present during preimplantation development. It was localised in the nucleus of uncommitted cells, from the cleavage stage up to the precursor epiblast, and corresponded with the presence of soluble CXADR3/7 splice variant. CAR was displayed on the membrane, involving in the formation of tight junction at compaction and blastocyst stages in both outer and inner cells, and CAR corresponded with the full-length CAR-containing transmembrane domain. In trophectodermal cells of hatched blastocysts, CAR was reduced in the membrane and concentrated in the nucleus, which correlated with the switch in RNA expression to the CXADR4/7 and CXADR2/7 splice variants. The cells in the outer layer of hESC colonies contained CAR on the membrane and all the cells of the colony had CAR in the nucleus, corresponding with the transmembrane CXADR and CXADR4/7. Upon differentiation of hESC into cells representing the three germ layers and trophoblast lineage, the expression of CXADR was downregulated. We concluded that CXADR is differentially expressed during human preimplantation development. We described various CAR expressions: i) soluble CXADR marking undifferentiated blastomeres; ii) transmembrane CAR related with epithelial-like cell types, such as the trophectoderm (TE) and the outer layer of hESC colonies; and iii) soluble CAR present in TE nuclei after hatching. The functions of these distinct forms remain to be elucidated.

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Section: Discussionmentioning

confidence: 99%

CAR expression in human embryos and hESC illustrates its role in pluripotency and tight junctions

Krivega¹,

Geens²,

Velde³

2014

Reproduction

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“…Horseradish peroxidase-labeled secondary antibodies were from Jackson ImmunoResearch (West Grove, PA). Rabbit anti-CAR-1605 and anti-CAR Ex8 -5678 have previously been described (10,11,14,28 (42). For Fluorescence Resonance Energy Transfer (FRET) and binding assays, MAGI-1 PDZ1, PDZ2, and PDZ3 domains and the CAR Ex8 C terminus were cloned (In-Fusion; Clontech) into a pGEX-6p vector (GE Healthcare, Piscataway, NJ) modified to contain a His tag upstream of the glutathione transferase (GST) tag (pHH2).…”

Section: Methodsmentioning

confidence: 99%

“…Previous work has shown that MAGI-1 is able to suppress CAR Ex8 expression in nonpolarized cells (11). We hypothesized that MAGI-1 may also regulate the levels of CAR Ex8 in polarized epithelia and, thus, regulate apical adenoviral infection.…”

mentioning

confidence: 89%

“…CAR has several alternatively spliced transcripts, two of which encode transmembrane splice forms: one that terminates after the seventh exon (CAR Ex7 ) and one that splices from a cryptic splice donor site within the seventh exon and terminates after the eighth exon (CAR Ex8 ) (11,32,34). These two isoforms differ only in the last 26 (CAR Ex7 ) or 13 (CAR Ex8 ) amino acids (aa) of the cytoplasmic domain, suggesting distinct interactions and functional roles.…”

mentioning

confidence: 99%

“…In polarized epithelial cells, CAR Ex7 resides on the basolateral surface and is thus sequestered from potential viral interactions on the apical surface (38,39). In contrast, although it is a less abundant isoform, CAR Ex8 can localize at the apical surface in primary airway epithelia where it can mediate adenovirus infection from the airway (11). The knowledge of the existence of an apical receptor results in a paradigm shift from the commonly held belief that there must be a transient or sustained break in the barrier for the virus to gain access to the basolateral receptor (3,4,36,44).…”

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confidence: 99%

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The PDZ1 and PDZ3 Domains of MAGI-1 Regulate the Eight-Exon Isoform of the Coxsackievirus and Adenovirus Receptor

Kolawole¹,

Sharma²,

Yan³

et al. 2012

J Virol

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cEpithelial integrity is essential for homeostasis and poses a formidable barrier to pathogen entry. Major factors for viral entry into epithelial cells are the localization and abundance of the primary receptor. The coxsackievirus and adenovirus receptor (CAR) is a primary receptor for these two pathogenic groups of viruses. In polarized epithelia, a low-abundance, alternatively spliced eight-exon isoform of CAR, CAR Ex8 , is localized apically where it can support viral infection from the air-exposed surface. Using biochemical, cell biology, genetic, and spectroscopic approaches, we show that the levels of apical CAR Ex8 are negatively regulated by the PDZ domain-containing protein MAGI-1 (membrane-associated guanylate kinase with inverted orientation protein-1) and that two MAGI-1 PDZ domains, PDZ1 and PDZ3, regulate CAR Ex8 levels in opposing ways. Similar to fulllength MAGI-1, expression of the isolated PDZ3 domain significantly reduces cell surface CAR Ex8 abundance and adenovirus infection. In contrast, the PDZ1 domain is able to rescue CAR Ex8 and adenovirus infection from MAGI-1-mediated suppression. These data suggest a novel cell-based strategy to either suppress viral infection or augment adenovirus-based gene therapy.

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The coxsackievirus and adenovirus receptor: virological and biological beauty

Excoffon

2020

FEBS Letters

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The coxsackievirus and adenovirus receptor (CAR) is an essential multifunctional cellular protein that is only beginning to be understood. CAR serves as a receptor for many adenoviruses, human group B coxsackieviruses, swine vesicular disease virus, and possibly other viruses. While named for its function as a viral receptor, CAR is also involved in cell adhesion, immune cell activation, synaptic transmission, and signaling. Knockout mouse models were first to identify some of these biological functions; however, tissue‐specific model systems have shed light on the complexity of different CAR isoforms and their specific activities. Many of these functions are mediated by the large number of interacting proteins described so far, and several new putative interactions have recently been discovered. As antiviral and gene therapy strategies that target CAR continue to emerge, future work poised to understand the biological implications of manipulating CAR in vivo is critical.

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Isoform-Specific Regulation and Localization of the Coxsackie and Adenovirus Receptor in Human Airway Epithelia

Cited by 61 publications

References 44 publications

CAR expression in human embryos and hESC illustrates its role in pluripotency and tight junctions

CAR expression in human embryos and hESC illustrates its role in pluripotency and tight junctions

The PDZ1 and PDZ3 Domains of MAGI-1 Regulate the Eight-Exon Isoform of the Coxsackievirus and Adenovirus Receptor

The coxsackievirus and adenovirus receptor: virological and biological beauty

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