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research-article
Author(s):
Zhuo-Zhuang Lu 1 ,
Hongjie Wang 1 ,
YiYi Zhang 1 ,
Hua Cao 1 ,
Zongyi Li 1 ,
Pascal Fender 2 , * ,
André Lieber 1 , 3 , *
Publication date (Electronic): 31 October 2013
Journal: PLoS Pathogens
Publisher: Public Library of Science
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Human adenovirus serotypes Ad3, Ad7, Ad11, and Ad14 use the epithelial junction protein desmoglein 2 (DSG2) as a receptor for infection. During Ad infection, the fiber and penton base capsid proteins are produced in vast excess and form hetero-oligomers, called pentons. It has been shown for Ad3 that pentons self-assemble into penton-dodecahedra (PtDd). Our previous studies with recombinant purified Ad3 PtDd (produced in insect cells) showed that PtDd bind to DSG2 and trigger intracellular signaling resulting in the transient opening of junctions between epithelial cells. So far, a definitive proof for a function of Ad3 PtDd in the viral life cycle is elusive. Based on the recently published 3D structure of recombinant Ad3 PtDd, we generated a penton base mutant Ad3 vector (mu-Ad3GFP). mu-Ad3GFP is identical to its wild-type counterpart (wt-Ad3GFP) in the efficiency of progeny virus production; however, it is disabled in the production of PtDd. For infection studies we used polarized epithelial cancer cells or cell spheroids. We showed that in wt-Ad3GFP infected cultures, PtDd were released from cells before viral cytolysis and triggered the restructuring of epithelial junctions. This in turn facilitated lateral viral spread of de novo produced virions. These events were nearly absent in mu-Ad3GFP infected cultures. Our in vitro findings were consolidated in mice carrying xenograft tumors derived from human epithelial cancer cells. Furthermore, we provide first evidence that PtDd are also formed by another DSG2-interacting Ad serotype, the newly emerged, highly pathogenic Ad14 strain (Ad14p1). The central finding of this study is that a subgroup of Ads has evolved to generate PtDd as a strategy to achieve penetration into and dissemination in epithelial tissues. Our findings are relevant for basic and applied virology, specifically for cancer virotherapy. We have recently reported that a group of human Ads uses DSG2 as a receptor for infection. Among the DSG2-interacting Ads is serotype 3, which is widely distributed in the human population. During Ad3 infection, subviral particles (PtDd) formed by two capsid proteins are produced in vast excess and released early in infection. In this study, we demonstrate that PtDd trigger the opening of epithelial junctions and thus support the lateral spread of Ad3 progeny virus in epithelial tissues. Our study contributes to a better understanding of Ad3 infection and pathology. It also has implications for Ad-mediated gene transfer into epithelial tissues and tumors. Abstract
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Most cited references30
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Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery.
S Futaki, T Suzuki, W Ohashi … (2001)
A basic peptide derived from human immunodeficiency virus (HIV)-1 Tat protein (positions 48-60) has been reported to have the ability to translocate through the cell membranes and accumulate in the nucleus, the characteristics of which are utilized for the delivery of exogenous proteins into cells. Based on the fluorescence microscopic observations of mouse macrophage RAW264.7 cells, we found that various arginine-rich peptides have a translocation activity very similar to Tat-(48-60). These included such peptides as the d-amino acid- and arginine-substituted Tat-(48-60), the RNA-binding peptides derived from virus proteins, such as HIV-1 Rev, and flock house virus coat proteins, and the DNA binding segments of leucine zipper proteins, such as cancer-related proteins c-Fos and c-Jun, and the yeast transcription factor GCN4. These segments have no specific primary and secondary structures in common except that they have several arginine residues in the sequences. Moreover, these peptides were able to be internalized even at 4 degrees C. These results strongly suggested the possible existence of a common internalization mechanism ubiquitous to arginine-rich peptides, which is not explained by a typical endocytosis. Using (Arg)(n) (n = 4-16) peptides, we also demonstrated that there would be an optimal number of arginine residues (n approximately 8) for the efficient translocation.
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Desmoglein 2 is a receptor for adenovirus serotypes 3, 7, 11, and 14
Hongjie Wang, Zongyi Li, Ying Liu … (2010)
We have identified desmoglein 2 (DSG2) as the primary high-affinity receptor used by adenovirus (Ad) serotypes Ad3, Ad7, Ad11, and Ad14. These serotypes represent important human pathogens causing respiratory tract infections. In epithelial cells, adenovirus binding to DSG2 triggers events reminiscent of epithelial-to-mesenchymal transition, leading to transient opening of intercellular junctions. This improves access to receptors, e.g. CD46 and Her2/neu, that are trapped in intercellular junctions. In addition to complete virions, dodecahedral particles (PtDd), formed by viral penton and fiber in excess during viral replication, can trigger DSG2-mediated opening of intercellular junctions as shown by studies with recombinant Ad3 PtDd. Our findings shed light on adenovirus biology and pathogenesis and have implications for cancer therapy.
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Clostridium perfringens Enterotoxin Fragment Removes Specific Claudins from Tight Junction Strands
Noriyuki Sonoda, Mikio Furuse, Hiroyuki Sasaki … (1999)
Claudins, comprising a multigene family, constitute tight junction (TJ) strands. Clostridium perfringens enterotoxin (CPE), a single ∼35-kD polypeptide, was reported to specifically bind to claudin-3/RVP1 and claudin-4/CPE-R at its COOH-terminal half. We examined the effects of the COOH-terminal half fragment of CPE (C-CPE) on TJs in L transfectants expressing claudin-1 to -4 (C1L to C4L, respectively), and in MDCK I cells expressing claudin-1 and -4. C-CPE bound to claudin-3 and -4 with high affinity, but not to claudin-1 or -2. In the presence of C-CPE, reconstituted TJ strands in C3L cells gradually disintegrated and disappeared from their cell surface. In MDCK I cells incubated with C-CPE, claudin-4 was selectively removed from TJs with its concomitant degradation. At 4 h after incubation with C-CPE, TJ strands were disintegrated, and the number of TJ strands and the complexity of their network were markedly decreased. In good agreement with the time course of these morphological changes, the TJ barrier (TER and paracellular flux) of MDCK I cells was downregulated by C-CPE in a dose-dependent manner. These findings provided evidence for the direct involvement of claudins in the barrier functions of TJs.
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Author and article information
Contributors
Michael J. Imperiale: Role: Editor
Journal
Journal ID (nlm-ta): PLoS Pathog
Journal ID (iso-abbrev): PLoS Pathog
Journal ID (publisher-id): plos
Journal ID (pmc): plospath
Title: PLoS Pathogens
Publisher: Public Library of Science (San Francisco, USA )
ISSN (Print): 1553-7366
ISSN (Electronic): 1553-7374
Publication date Collection: October 2013
Publication date (Print): October 2013
Publication date (Electronic): 31 October 2013
Volume: 9
Issue: 10
Electronic Location Identifier: e1003718
Affiliations
[1 ]University of Washington, Division of Medical Genetics, Seattle, Washington, United States of America
Author notes
* E-mail: pfender@ 123456embl.fr (PF); lieber00@ 123456u.washington.edu (AL)
Article
Publisher ID: PPATHOGENS-D-13-01651
DOI: 10.1371/journal.ppat.1003718
PMC ID: 3814681
PubMed ID: 24204268
SO-VID: 849b0825-a6d5-49f9-94c9-ac4885274ab8
Copyright statement: Copyright @ 2013
License:
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
History
Date received : 20 June 2013
Date accepted : 4 September 2013
Page count
Pages: 16
Funding
The work was funded by NIH grants R01 CA080192 and R01 HLA078836. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Categories
Subject: Research Article
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