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Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11 and 14

Abstract

We have identified desmoglein-2 (DSG-2) as the primary high-affinity receptor used by adenoviruses Ad3, Ad7, Ad11 and Ad14. These serotypes represent key human pathogens causing respiratory and urinary tract infections. In epithelial cells, adenovirus binding of DSG-2 triggers events reminiscent of epithelial-to-mesenchymal transition, leading to transient opening of intercellular junctions. This opening improves access to receptors, for example, CD46 and Her2/neu, that are trapped in intercellular junctions. In addition to complete virions, dodecahedral particles (PtDds), formed by excess amounts of viral capsid proteins, penton base and fiber during viral replication, can trigger DSG-2–mediated opening of intercellular junctions as shown by studies with recombinant Ad3 PtDds. Our findings shed light on adenovirus biology and pathogenesis and may have implications for cancer therapy.

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Figure 1: Identification of receptor X using Ad3 virions and Ad3 PtDds.
Figure 2: Validation of DSG-2 as adenovirus receptor by loss-of-function studies.
Figure 3: Validation of DSG-2 as adenovirus receptor by gain-of-function studies.
Figure 4: DSG-2 localization in human epithelial cells and interaction with Ad3.
Figure 5: EMT signaling induced by Ad3 virions and PtDds in epithelial cells.
Figure 6: Opening of intercellular junctions in epithelial breast cancer cells by interaction of Ad3 virions or PtDds with DSG-2.

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Acknowledgements

This work was supported by US National Institutes of Health grants R01 CA080192 and R01 HLA078836 and Pacific Ovarian Cancer Research Consortium/Specialized Program of Research Excellence in Ovarian Cancer Grant P50 CA83636. We thank R. van Rensburg for critical comments and the Functional Genomics Core at the Center for Ecogenetics and Environmental Health, School of Public Health University of Washington for array analysis.

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Authors

Contributions

H.W. conducted the studies for the identification and validation of DSG-2 as an adenovirus receptor; Z.-Y.L. performed the immunofluorescence studies; Y.L. performed the in vivo studies; J.P. contributed to adenovirus attachment assays; I.B. contributed to in vivo studies; T.M. helped with the expression array studies; D.K. and M.R.D. participated in in vitro studies with Herceptin; R.S. performed the western blot studies for kinase activation; X.-B.Z. produced the DSG-2–expressing lentivirus vector; J.K.W. III provided the DSG-2–specific antibodies; N.U. and C.D. provided tumor biopsies; A.H. helped with data interpretation; P.F. performed the Biacore studies and provided recombinant PtDds, and A.L. supervised the project and wrote the manuscript.

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Correspondence to André Lieber.

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Wang, H., Li, ZY., Liu, Y. et al. Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11 and 14. Nat Med 17, 96–104 (2011). https://doi.org/10.1038/nm.2270

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