Insights into adenovirus host cell interactions from structural studies

Nemerow, Glen R.; Pache, Lars; Reddy, Vijay; Stewart, Phoebe L.

doi:10.1016/j.virol.2008.10.016

Cited by 91 publications

(87 citation statements)

References 82 publications

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“…To track broken membranes, we expressed mCherry-Gal3 fusion protein in HeLa cells, followed by continuous infection with HAdV-C5 or HAdV-B3 for 1h. HAdV-C5 enters epithelial cells through CAR and integrin receptors, and HAdV-B3 through CD46 and desmoglein-2 receptors [3] [47] [48] [49]. Both viruses penetrate HeLa cells independent of endosomal acidification with an efficiency higher than 70% (HAdV-C5) or about 40% (HAdV-B3) within 30 min of cold-synchronized infection [30].…”

Section: Resultsmentioning

confidence: 99%

Endosomophagy clears disrupted early endosomes but not virus particles during virus entry into cells     

Luisoni

Bauer

Bartenschlager

et al. 2016

Matters

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Enveloped viruses fuse with host membranes without affecting cell integrity. Nonenveloped viruses and bacteria penetrate by rupturing endosomal membranes and thus expose complex-type carbohydrates from the endosome lumen to cytosolic proteins. Here we report on the dynamics and initial marker analyses of Galectin-3 (Gal3)-positive membranes triggered by incoming adenovirus species B/C in HeLa cells. Using mCherry-Gal3 reporter constructs, immunolabeling, confocal and electron microscopy, we detected robust signals from Gal3-containing, early endosomal antigen 1-positive membranes 1 h post-infection (pi). Adenoviruses penetrate from non-acidic endosomes with high efficiency, 15 min pi, and largely outnumbered the Gal3-positive membranes, suggesting that Gal3 recruitment to broken membranes is transient, or Gal3-positive membranes are rapidly turned-over. In support of rapid turn-over, Gal3 was found within single-membrane vesicles and degradative autophagosomes. The Gal3 membranes contained ubiquitin and the poly-ubiquitin binding protein p62/sequestosome-1, but only low amounts of virus, or membrane-lytic protein VI exposed from virions. Remarkably, the Gal3-positive membranes were cleared 3 h pi, slower than protein VI, which was cleared 30 min pi. The data show that broken early endosomes, but not virus particles, are rapidly removed by a process involving autophagy, which we term 'endosomophagy'. We speculate that endosomophagy is pro-viral and attenuates innate immunity.

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Section: Resultsmentioning

confidence: 99%

Endosomophagy clears disrupted early endosomes but not virus particles during virus entry into cells     

Luisoni

Bauer

Bartenschlager

et al. 2016

Matters

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“…The fiber protein consists of a tail for anchorage to the penton base, a shaft of variable length, and a globular fiber knob (FK). The latter is responsible for the binding of the virus particle (vp) to a primary attachment receptor (43). Species B Ads bind a different cell surface receptor(s) than do most of the other species members (76).…”

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confidence: 99%

Avidity Binding of Human Adenovirus Serotypes 3 and 7 to the Membrane Cofactor CD46 Triggers Infection

Trinh

Lesage

Chennamparampil

et al. 2012

J Virol

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The species B human adenoviruses (HAdVs) infect cells upon attaching to CD46 or desmoglein 2 (DSG-2) by one or several of their 12 fiber knob trimers (FKs). To test whether DSG-2 and CD46 simultaneously serve as virus receptors for adenovirus type 3 (Ad3), we performed individual and combined CD46/DSG-2 loss-of-function studies in human lung A549 and 16HBE14o cells. Our results suggest that in these cells, DSG-2 functions as a major attachment receptor for Ad3, whereas CD46 exerts a minor contribution to virus attachment and uptake in the range of ϳ10%. However, in other cells the role of CD46 may be more pronounced depending on, e.g., the expression levels of the receptors. To test if avidity allows Ad3/7 to use CD46 as a receptor, we performed gain-of-function studies. The cell surface levels of ectopically expressed CD46 in CHO or human M010119 melanoma cells lacking DSG-2 positively correlated with Ad3/7 infections, while Ad11/35 infections depended on CD46 but less on CD46 levels. Antibody-cross-linked soluble CD46 blocked Ad3/7/11/35 infections, while soluble CD46 alone blocked Ad11/35 but not Ad3/7. Soluble Ad3/7-FKs poorly inhibited Ad3/7 infection of CHO-CD46 cells, illustrating that Ad3/7-FKs bind with low affinity to CD46. This was confirmed by Biacore studies. Ad3/7-FK binding to immobilized CD46 at low density was not detected, unlike that of Ad11/35-FK. At higher CD46 densities, however, Ad3/7-FK bound to CD46 with only 15-fold-higher dissociation constants than those of Ad11/35-FK. These data show that an avidity mechanism for Ad3/7 binding to CD46 leads to infection of CD46-positive cells.

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“…In addition, Ads have demonstrated great potential as vaccine vectors (7,13,22). Ad has a large, complex, icosahedral capsid with a diameter of ϳ920 Å, not including the elongated homotrimeric fibers at each of its 5-fold vertices.…”

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confidence: 99%

Conserved Fiber-Penton Base Interaction Revealed by Nearly Atomic Resolution Cryo-Electron Microscopy of the Structure of Adenovirus Provides Insight into Receptor Interaction

Cao

Dong²,

Wu³

et al. 2012

J Virol

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c Adenovirus (Ad) cell attachment is initiated by the attachment of the fiber protein to a primary receptor (usually CAR or CD46). This event is followed by the engagement of the penton base protein with a secondary receptor (integrin) via its loop region, which contains an Arg-Gly-Asp (RGD) motif, to trigger virus internalization. To understand the well-orchestrated adenovirus cell attachment process that involves the fiber and the penton base, we reconstructed the structure of an Ad5F35 capsid, comprising an adenovirus type 5 (Ad5) capsid pseudotyped with an Ad35 fiber, at a resolution of approximately 4.2 Å. The fiber-penton base interaction in the cryo-electron microscopic (cryo-EM) structure of Ad5F35 is similar to that in the cryo-EM structure of Ad5, indicating that the fiber-penton base interaction of adenovirus is conserved. Our structure also confirms that the C-terminal segment of the fiber tail domain constitutes the bottom trunk of the fiber shaft. Based on the conserved fiber-penton base interaction, we have proposed a model for the interaction of Ad5F35 with its primary and secondary receptors. This model could provide insight for designing adenovirus gene delivery vectors. Human adenoviruses (Ads) are nonenveloped, double-stranded DNA viruses and are responsible for respiratory, gastrointestinal, and ocular infections. In addition, Ads have demonstrated great potential as vaccine vectors (7,13,22). Ad has a large, complex, icosahedral capsid with a diameter of ϳ920 Å, not including the elongated homotrimeric fibers at each of its 5-fold vertices. The Ad capsid is composed of three major proteins: 240 hexon trimers that form the 20 facets of the icosahedral capsid, 12 penton bases, and 12 fiber trimers at the 12 icosahedral vertices (8, 36). A structure of Ad5F35, comprising an adenovirus type 5 (Ad5) capsid pseudotyped with an Ad35 fiber (25, 35), has been determined at 6-Å resolution (33). Combined with secondary structure prediction for minor proteins, the 6-Å structure has enabled the precise locations of minor proteins IIIa, VI, VIII, and IX to be determined (33). The locations of these minor proteins have been further confirmed by two nearly atomic resolution Ad structural analyses: the Ad5 structure analyzed by cryoelectron microscopy (cryo-EM) and the Ad5F35 structure determined using X-ray crystallography (17, 30). The minor capsid proteins, including IIIa, VIII, and IX, are thought to form proteinprotein networks to enhance the stability of the Ad capsid (17).The Ad fiber, which is formed by three copies of fiber proteins, plays a role in the initial attachment of the Ad capsid to the host cell surface through its interaction with the cellular receptor. Although Ad fibers are of various lengths depending on the serotype, the fiber proteins of all serotypes share an overall architecture: an N-terminal tail domain that interacts with the pentameric penton base, a C-terminal globular knob domain that functions as the attachment site for the host cell receptors, and a central shaft domain th...

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Insights into adenovirus host cell interactions from structural studies

Cited by 91 publications

References 82 publications

Endosomophagy clears disrupted early endosomes but not virus particles during virus entry into cells

Endosomophagy clears disrupted early endosomes but not virus particles during virus entry into cells

Avidity Binding of Human Adenovirus Serotypes 3 and 7 to the Membrane Cofactor CD46 Triggers Infection

Conserved Fiber-Penton Base Interaction Revealed by Nearly Atomic Resolution Cryo-Electron Microscopy of the Structure of Adenovirus Provides Insight into Receptor Interaction

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Insights into adenovirus host cell interactions from structural studies

Cited by 91 publications

References 82 publications

Endosomophagy clears disrupted early endosomes but not virus particles during virus entry into cells&nbsp; &nbsp; &nbsp;

Endosomophagy clears disrupted early endosomes but not virus particles during virus entry into cells&nbsp; &nbsp; &nbsp;

Avidity Binding of Human Adenovirus Serotypes 3 and 7 to the Membrane Cofactor CD46 Triggers Infection

Conserved Fiber-Penton Base Interaction Revealed by Nearly Atomic Resolution Cryo-Electron Microscopy of the Structure of Adenovirus Provides Insight into Receptor Interaction

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Endosomophagy clears disrupted early endosomes but not virus particles during virus entry into cells

Endosomophagy clears disrupted early endosomes but not virus particles during virus entry into cells