Prevention of viral-induced respiratory disease begins with an understanding of the factors that increase or decrease susceptibility to viral infection. The primary receptor for most adenoviruses is the coxsackievirus and adenovirus receptor (CAR), a cell-cell adhesion protein normally localized at the basolateral surface of polarized epithelia and involved in neutrophil transepithelial migration. Recently, an alternate isoform of CAR, CAREx8, has been identified at the apical surface of polarized airway epithelia and is implicated in viral infection from the apical surface. We hypothesized that the endogenous role of CAREx8 may be to facilitate host innate immunity. We show that IL-8, a proinflammatory cytokine and a neutrophil chemoattractant, stimulates the protein expression and apical localization of CAREx8 via activation of AKT/S6K and inhibition of GSK3β. Apical CAREx8 tethers infiltrating neutrophils at the apical surface of a polarized epithelium. Moreover, neutrophils present on the apical-epithelial surface enhance adenovirus entry into the epithelium. These findings suggest that adenovirus evolved to co-opt an innate immune response pathway that stimulates the expression of its primary receptor, apical CAREx8, to allow the initial infection the intact epithelium. In addition, CAREx8 is a new target for the development of novel therapeutics for both respiratory inflammatory disease and adenoviral infection.
The human poliovirus receptor (PVR) is a cell surface protein with a multitude of functions in human biology. PVR was initially identified as the receptor for the human poliovirus and recent discoveries have given a greater insight into both its morphology and its function. Alternative splicing of the PVR gene results in a total of 4 alternatively spliced isoforms. Two of these isoforms lack a complete transmembrane domain and are considered soluble and block viral infection; the remaining two transmembrane isoforms differ only at their extreme C-terminal domains resulting in differential localization in epithelia and polarity of viral infection. In addition to its role as a receptor for the human poliovirus, several native biological functions have also been uncovered. PVR is an important cell adhesion protein and is involved in the transendothelial migration of leukocytes. Through its interactions with CD226 and TIGIT, transmembrane proteins found on leukocytes, PVR is a key regulator of the cell-mediated immune response. As PVR is differentially regulated in a broad spectrum of cancers, it has a strong potential for clinical use as a biomarker. PVR is also a possible target for novel cancer therapies. Utilizing its natural tropism for PVR, a genetically modified form of the live attenuated poliovirus vaccine is currently being tested for its ability to locate and destroy certain tumors. These recent studies emphasize the importance of PVR in human biology and demonstrate its utility beyond being a viral receptor protein.
A variety of metastatic cancer cells use actin-rich membrane protrusions, known as invadopodia, for efficient ECM degradation, which involves trafficking of proteases from intracellular compartments to these structures. Here, we demonstrate that in the metastatic breast cancer cell line MDA-MB-231, retromer regulates the matrix invasion activity by recycling matrix metalloprotease, MT1-MMP. We further found that MT2-MMP, another abundantly expressed metalloprotease, is also invadopodia associated. MT1- and MT2-MMP showed a high degree of colocalization but were located on the distinct endosomal domains. Retromer and its associated sorting nexin, SNX27, phenocopied each other in matrix degradation via selectively recycling MT1-MMP but not MT2-MMP. ITC-based studies revealed that both SNX27 and retromer could directly interact with MT1-MMP. Analysis from a publicly available database showed SNX27 to be overexpressed or frequently altered in the patients having invasive breast cancer. In xenograft-based studies, SNX27-depleted cell lines showed prolonged survival of SCID mice, suggesting a possible implication for overexpression of the sorting nexin in tumor samples.
UVB wavelengths of light induce the formation of photoproducts in genomic DNA that are potentially mutagenic and detrimental to epidermal cell function. The mineralocorticoid and androgen receptor antagonist spironolactone (SP) was recently identified as an inhibitor of UV photoproduct removal in human cancer cells in vitro via its ability to promote the rapid proteolytic degradation of the DNA repair protein XPB. Using normal human keratinocytes in vitro and skin explants ex vivo, we found that SP rapidly depleted XPB protein in both systems and abrogated two major responses to UVB-induced DNA damage, including the removal of UV photoproducts from genomic DNA and the activation of ATR/ATM DNA damage kinase signaling. These effects were also correlated with both mutagenesis and a predisposition to UVB-induced cell death but were unique to SP, because neither the SP metabolites canrenone and 7α-thiomethylspironolactone nor the more specific mineralocorticoid receptor antagonist eplerenone affected XPB protein levels or the UVB response. Our findings provide an approach for studying XPB and its roles in the UVB DNA damage response in human skin ex vivo and indicate that SP may increase UVB mutagenesis and skin cancer risk in certain individuals.
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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