Synchronized Retrovirus Fusion in Cells Expressing Alternative Receptor Isoforms Releases the Viral Core into Distinct Sub-cellular Compartments
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Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/331077", "https://ndownloader.figshare.com/files/331124", "https://ndownloader.figshare.com/files/331178", "https://ndownloader.figshare.com/files/331223", "https://ndownloader.figshare.com/files/331262", "https://ndownloader.figshare.com/files/331303", "https://ndownloader.figshare.com/files/331339", "https://ndownloader.figshare.com/files/331375", "https://ndownloader.figshare.com/files/331409", "https://ndownloader.figshare.com/files/331452", "https://ndownloader.figshare.com/files/331507", "https://ndownloader.figshare.com/files/331569"], "description"=>"<div><p>Disparate enveloped viruses initiate infection by fusing with endosomes. However, the highly diverse and dynamic nature of endosomes impairs mechanistic studies of fusion and identification of sub-cellular sites supporting the nucleocapsid release. We took advantage of the extreme stability of avian retrovirus-receptor complexes at neutral pH and of acid-dependence of virus-endosome fusion to isolate the latter step from preceding asynchronous internalization/trafficking steps. Viruses were trapped within endosomes in the presence of NH<sub>4</sub>Cl. Removal of NH<sub>4</sub>Cl resulted in a quick and uniform acidification of all subcellular compartments, thereby initiating synchronous viral fusion. Single virus imaging demonstrated that fusion was initiated within seconds after acidification and often culminated in the release of the viral core from an endosome. Comparative studies of cells expressing either the transmembrane or GPI-anchored receptor isoform revealed that the transmembrane receptor delivered the virus to more fusion-permissive compartments. Thus the identity of endosomal compartments, in addition to their acidity, appears to modulate viral fusion. A more striking manifestation of the virus delivery to distinct compartments in the presence of NH<sub>4</sub>Cl was the viral core release into the cytosol of cells expressing the transmembrane receptor and into endosomes of cells expressing the GPI-anchored isoform. In the latter cells, the newly released cores exhibited restricted mobility and were exposed to a more acidic environment than the cytoplasm. These cores appear to enter into the cytosol after an additional slow temperature-dependent step. We conclude that the NH<sub>4</sub>Cl block traps the virus within intralumenal vesicles of late endosomes in cells expressing the GPI-anchored receptor. Viruses surrounded by more than one endosomal membrane release their core into the cytoplasm in two steps – fusion with an intralumenal vesicle followed by a yet unknown temperature-dependent step that liberates the core from late endosomes.</p> </div>", "links"=>[], "tags"=>["synchronized", "retrovirus", "fusion", "cells", "expressing", "receptor", "isoforms", "releases", "viral", "sub-cellular", "compartments"], "article_id"=>125357, "categories"=>["Biological Sciences"], "users"=>["Sergi Padilla-Parra", "Mariana Marin", "Naoyuki Kondo", "Gregory B. Melikyan"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002694.s001", "https://dx.doi.org/10.1371/journal.ppat.1002694.s002", "https://dx.doi.org/10.1371/journal.ppat.1002694.s003", "https://dx.doi.org/10.1371/journal.ppat.1002694.s004", "https://dx.doi.org/10.1371/journal.ppat.1002694.s005", "https://dx.doi.org/10.1371/journal.ppat.1002694.s006", "https://dx.doi.org/10.1371/journal.ppat.1002694.s007", "https://dx.doi.org/10.1371/journal.ppat.1002694.s008", "https://dx.doi.org/10.1371/journal.ppat.1002694.s009", "https://dx.doi.org/10.1371/journal.ppat.1002694.s010", "https://dx.doi.org/10.1371/journal.ppat.1002694.s011", "https://dx.doi.org/10.1371/journal.ppat.1002694.s012"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Synchronized_Retrovirus_Fusion_in_Cells_Expressing_Alternative_Receptor_Isoforms_Releases_the_Viral_Core_into_Distinct_Sub_cellular_Compartments/125357", "title"=>"Synchronized Retrovirus Fusion in Cells Expressing Alternative Receptor Isoforms Releases the Viral Core into Distinct Sub-cellular Compartments", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-05-10 01:29:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/640887"], "description"=>"<p>(A) Micrograph showing single ASLV pseudoviruses co-labeled with Gag-GFP (green) and DiD (red) following the incubation with cells expressing TVA800 for 40 min at 37°C in isotonic HBSS supplemented with 70 mM NH<sub>4</sub>Cl (left panel). Removal of NH<sub>4</sub>Cl through perfusion with HBSS caused a marked decrease in the GFP signal, but not in DiD fluorescence (middle). Upon returning to NH<sub>4</sub>Cl (right), the GFP fluorescence of fusion-incompetent particles fully recovered (#1, arrowhead), whereas the signal from fused particles remained undetectable (#2, arrow). The viral core release into the cytosol is manifested in spatial separation of green and red puncta (#3, double arrowhead). Cell nuclei are labeled with Hoescht (blue). Scale bar is 15 µm. (B–G) ASLV pseudoviruses co-labeled with Gag-GFP and DiD were internalized by CV-1 cells expressing TVA950 (B, D, F) or TVA800 (C, E, G) in the presence of NH<sub>4</sub>Cl, and virus-endosome fusion was initiated by perfusion with HBSS, as described in <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002694#s4\" target=\"_blank\">Materials and Methods</a>. (B, C) The fluorescence intensity profiles corresponding to particles that failed to fuse following the arrest/release protocol, as evidenced by complete recovery of the GFP signal. (D, E) Examples of complete loss of the GFP marker from virions. (F, G) Partial release of the content marker. Cells were initially perfused with 70 mM NH<sub>4</sub>Cl in HBSS (white thick horizontal bars at the top of each graph) followed by perfusion with plain HBSS for 2 min (black horizontal bars) and returned to NH<sub>4</sub>Cl. The mean intensities of GFP and DiD fluorescence from single particles are shown (green and red circles, respectively). Pink lines show the changes in the intraviral pH upon removal of NH<sub>4</sub>Cl (for details, see <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002694#ppat.1002694.s001\" target=\"_blank\">Figures. S1</a> and <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002694#ppat.1002694.s002\" target=\"_blank\">S2</a>). Kymographs illustrating the time-dependent changes in the mean GFP and DID signals (overlaid) are also shown above each plot. An irreversible transition from yellow (co-localized GFP and DiD signals) to red (DiD only) manifests the release of the GFP-based content marker into the cytosol. Diagrams of the fusion outcomes (reversible GFP quenching by acidic pH, full and partial release of the content marker) for respective panels are shown on the right.</p>", "links"=>[], "tags"=>["synchronous", "triggering", "aslv", "pseudovirus", "fusion", "endosomes"], "article_id"=>311372, "categories"=>["Biological Sciences"], "users"=>["Sergi Padilla-Parra", "Mariana Marin", "Naoyuki Kondo", "Gregory B. Melikyan"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002694.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Arrest_and_synchronous_triggering_of_ASLV_pseudovirus_fusion_with_endosomes_using_NH_4_Cl_/311372", "title"=>"Arrest and synchronous triggering of ASLV pseudovirus fusion with endosomes using NH<sub>4</sub>Cl.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:22:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/641045"], "description"=>"<p>(A) Spatial separation of the GFP- and DiD-tagged puncta following the NH<sub>4</sub>Cl arrest/release protocol. Double-labeled viruses were internalized by TVA950 (top panel) and TVA800 (bottom panel) cells in the presence of NH<sub>4</sub>Cl. Fusion was triggered by replacing NH<sub>4</sub>Cl with HBSS for 2 min (black horizontal bars) through local perfusion, and cells were returned to NH<sub>4</sub>Cl. Following the initial decay in the GFP fluorescence due to a partial release of the content marker, co-labeled particles split in two and continued to drift apart. The GFP signal partially recovered during the HBSS perfusion in TVA950 cells, but not TVA800 cells where recovery occurred only after returning to NH<sub>4</sub>Cl. Scale bar is 0.15 µm. (B, C) Separation of green (Gag-GFP) and red (DiD) puncta in NH<sub>4</sub>Cl-arrested TVA950 (B, video S3) and TVA800 (C, video S4) cells during perfusion with HBSS. The graphs show changes of the mean intensity of green and red signals for single particles shown in panel A. A drop in the red signal during the HBSS perfusion (marked by a blue asterisk) occurs due to the separation of formerly co-localized red and green puncta. The changes in cytosolic (B, E) and endosomal (C, F) pH during the HBSS perfusion measured in separate experiments (for details, see <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002694#ppat.1002694.s002\" target=\"_blank\">Figure S2</a>) are shown by pink lines. (D) Kinetics of spatial separation of SVPs and the viral membrane triggered by a 2 min-perfusion with HBSS (black horizontal bar and vertical dashed lines). Cumulative probabilities of core release as a function of time are plotted for TVA800 (filled circles) and TVA950 (open circles) cells. (E, F) Late spatial separation events occurring at the end or after the first HBSS pulse (horizontal black bars above each plot). The SVP release in a TVA950 cell (E, asterisk) was followed by partial recovery of the Gag-GFP fluorescence during the second HBSS perfusion, which paralleled the increase in the cytosolic pH (pink line). A spike in the DiD signal at the beginning of the second HBSS pulse in panel D occurred due to a transient overlap between separated puncta. The late SVP release events in TVA800 cells (F) did not exhibit the Gag-GFP signal recovery in the course of HBSS perfusion. The two-dimensional trajectories of the recipient endosomes (red) and the GFP-tagged sub-viral particles (green) obtained by single particle tracking are shown under for each respective panel. The beginning and the end of trajectories are marked by triangles and circles, respectively. A diagram showing the viral content and core release (spatial separation from the membrane) as a result of fusion are shown on the right.</p>", "links"=>[], "tags"=>["gfp-tagged", "viral", "cores", "membranes"], "article_id"=>311535, "categories"=>["Biological Sciences"], "users"=>["Sergi Padilla-Parra", "Mariana Marin", "Naoyuki Kondo", "Gregory B. Melikyan"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002694.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Spatial_separation_of_the_GFP_tagged_viral_cores_from_membranes_as_a_result_of_fusion_/311535", "title"=>"Spatial separation of the GFP-tagged viral cores from membranes as a result of fusion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:25:35"}
  • {"files"=>["https://ndownloader.figshare.com/files/641188"], "description"=>"<p>(A, B) Examples of the mean square displacement (MSD) as a function of time for GFP-tagged (green circles) and DiD-tagged (red circles) particles in TVA950 (A) and TVA800 (B) cells. Blue asterisks mark spatial separation of cores from membranes that coincided with an abrupt increase in the MSD slope for SVPs (green), while the movement pattern of DiD-recipient endosomes did not change significantly. (C) Representative MSD curves after SVP release are shown for five SVPs in TVA950 cells (black lines) and in TVA800 cells (red lines). (D) Log-log plot showing the mean MSD slopes and standard deviations for 15 SVP trajectories after core release in TVA950 (black) and TVA800 (red) cells each. (E) Distributions of diffusion coefficients for endosomes and viral particles before and after SVP release. Diffusion coefficients were calculated, as detailed in the <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002694#s4\" target=\"_blank\">Materials and Methods</a>. Box plots together with the Gaussian distribution for the diffusion values (circles and solid lines) corresponding to 18 endosomes (“DiD post-fusion”, red circles) and SVPs (“GFP post-fusion”, green circles) after core release are shown for TVA800 and TVA950 cells. Diffusion coefficients of three SVPs that were judged to be released into endosomal compartments of TVA950 cells are colored black (under “GFP post-fusion”). For comparison, the motility of 10 non-fusogenic particles trapped in endosomes after perfusion with HBSS is shown (“GFP, no fusion”, yellow circles). In addition, the diffusion coefficients for 10 not fused particles in the presence of the inhibitory peptide R99 is shown (blue circles). The diffusion coefficients of endosomes tagged with YFP-Rab7 (n = 20) and CFP-Rab5 (n = 20) in TVA800 and TVA950 cells (pooled data) are shown by magenta and cyan triangles, respectively.</p>", "links"=>[], "tags"=>["particles", "released", "aslv-endosome", "fusion"], "article_id"=>311676, "categories"=>["Biological Sciences"], "users"=>["Sergi Padilla-Parra", "Mariana Marin", "Naoyuki Kondo", "Gregory B. Melikyan"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002694.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Sub_viral_particles_released_by_ASLV_endosome_fusion_exhibit_increased_mobility_/311676", "title"=>"Sub-viral particles released by ASLV-endosome fusion exhibit increased mobility.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:27:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/641357"], "description"=>"<p>(A) TVA950 cells co-expressing CFP-Rab5 (green) and YFP-Rab7 (red) before (top row) and after (bottom row) incubation with 70 mM NH<sub>4</sub>Cl for 40 minutes at 37°C. Enlarged endosomes positive for Rab5 (diameter 12 µm) and Rab7 (diameter 15 µm) are indicated by arrowheads and arrows, respectively. Scale bars are 20 µm. (B) Same as in panel A, but for TVA800 cells. Enlarged endosomes positive for Rab5 (diameter 3.5 µm) and Rab7 (diameter 5 µm) are indicated by arrowheads and arrows, respectively. Scale bar 15 µm.</p>", "links"=>[], "tags"=>["creates"], "article_id"=>311856, "categories"=>["Biological Sciences"], "users"=>["Sergi Padilla-Parra", "Mariana Marin", "Naoyuki Kondo", "Gregory B. Melikyan"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002694.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NH_4_Cl_arrest_creates_large_endosomes_/311856", "title"=>"NH<sub>4</sub>Cl arrest creates large endosomes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:30:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/641549"], "description"=>"<p>Cells co-transfected with CFP-Rab5 (cyan) and YFP-Rab7 (green) were allowed to internalize ASLV pseudoviruses labeled with Gag-mKate2 (red) for 40 minutes at 37°C in the presence of 70 mM NH<sub>4</sub>Cl. (A) Image projections obtained from 30 confocal slices show viruses in a TVA950 cell expressing CFP-Rab5 and YFP-Rab7. Arrowheads show viral particles co-localized with Rab5-positive puncta. A rectangular region of interest, R0I (10×9 µm) encompassing a viral particle (upper left panel) is enlarged and shown in the lower panel. ROI is a confocal slice corresponding to the maximum intensity in Z for the red channel (Gag-mKate2). (B) Same as in panel A, but for TVA800 cell co-transfected with CFP-Rab5 and YFP-Rab7. Arrowheads show viral particles co-localized with Rab7-positive endosomes. A blow up view of ROI encompassing an internalized virus is shown in the lower panel. Co-localization analysis was done by constructing a line histogram (A and B, lower right panels) for a chosen confocal plane that showed a maximum intensity for all channels (ROIs in A and B). The line histogram shows the changes in fluorescence intensities for all three channels along the white lines (lower middle panels) drawn across the viruses and an endosomal compartment in the ROI (10×9 µm). Local maxima for Rab5 and/or Rab7 coinciding with the maximum of the mKate2 signal were counted as co-localization. Scale bars are 10 µm. (C) Summary of analyses of ASLV pseudovirus co-localization with endosomal markers in TVA950 (left) and TVA800 (right) cells.</p>", "links"=>[], "tags"=>["aslv", "preferentially", "resides", "rab5-positive", "endosomes", "tva950", "cells", "rab7-positive", "compartments", "tva800"], "article_id"=>312028, "categories"=>["Biological Sciences"], "users"=>["Sergi Padilla-Parra", "Mariana Marin", "Naoyuki Kondo", "Gregory B. Melikyan"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002694.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NH_4_Cl_arrested_ASLV_preferentially_resides_in_Rab5_positive_endosomes_in_TVA950_cells_and_in_Rab7_positive_compartments_in_TVA800_cells_/312028", "title"=>"NH<sub>4</sub>Cl-arrested ASLV preferentially resides in Rab5-positive endosomes in TVA950 cells and in Rab7-positive compartments in TVA800 cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:33:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/641674"], "description"=>"<p>(A) Schematic diagram of the NH<sub>4</sub>Cl arrest/chase experiments. EnvΔCT/BlaM-Vpr pseudoviruses were bound to either TVA950 (B) or TVA800 (C) cells at 4°C. Cells were allowed to internalize virus during 45 min at 37°C in the presence of 70 mM NH<sub>4</sub>Cl (yellow line in A). Fusion was initiated by transferring the cells into HBSS supplemented with 50 µg/ml R99 (blue line in A) for varied times and stopped either by adding back NH<sub>4</sub>Cl containing 50 µg/ml R99 (black circles) or by placing the samples on ice (TB) (red circles). At the end of the chase, cells were chilled on ice, loaded with the BlaM substrate and incubated overnight at 12°C. Data points are means and SEM of combined triplicate measurements from two independent experiments.</p>", "links"=>[], "tags"=>["progression", "acid-", "temperature-dependent", "steps", "fusion"], "article_id"=>312169, "categories"=>["Biological Sciences"], "users"=>["Sergi Padilla-Parra", "Mariana Marin", "Naoyuki Kondo", "Gregory B. Melikyan"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002694.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ASLV_progression_through_acid_and_temperature_dependent_steps_of_fusion_after_removal_of_the_NH_4_Cl_block_/312169", "title"=>"ASLV progression through acid- and temperature-dependent steps of fusion after removal of the NH<sub>4</sub>Cl block.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:36:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/641778"], "description"=>"<p>Alternative receptor isoforms direct ASLV entry through distinct pathways that culminate in fusion with early endosomes. Normal entry pathways through TVA800 and TVA950 may converge to early endosomes where mildly acidic pH initiates the viral content release, albeit with different efficiency <a href=\"http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002694#ppat.1002694-Jha1\" target=\"_blank\">[17]</a>. In the presence of NH<sub>4</sub>Cl (gray arrows), the virus bypasses early endosomes and enters intermediate compartments of TVA950 cells and late endosome-like compartments of TVA800 cells. Removal of NH<sub>4</sub>Cl initiates fusion with the limiting membrane of intermediate endosomes in TVA950 cells. Subsequent dilation of a fusion pore releases the viral core (triangle) into the cytosol. In TVA800 cells, ASLV is trapped within a small intralumenal vesicle, which is enclosed by a larger vesicle surrounded by the limiting membrane of an endosome. Fusion results in the content and core release into a large intralumenal vesicle. The viral core then traverses two membranes <i>via</i> back-fusion of an enlarge vesicle with the limiting membrane of an endosome (dashed arrow). The latter step is likely to be temperature-dependent and independent of ASLV Env.</p>", "links"=>[], "tags"=>["aslv", "fusion", "cells", "expressing", "receptors"], "article_id"=>312266, "categories"=>["Biological Sciences"], "users"=>["Sergi Padilla-Parra", "Mariana Marin", "Naoyuki Kondo", "Gregory B. Melikyan"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002694.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_for_ASLV_fusion_with_cells_expressing_alternative_receptors_following_the_arrest_release_protocol_/312266", "title"=>"Model for ASLV fusion with cells expressing alternative receptors following the arrest/release protocol.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-05-10 00:37:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/641847"], "description"=>"<p>The relative frequency of fusion outcomes was determined by pooling data from at least 4 independent experiments.</p>", "links"=>[], "tags"=>["synchronized", "aslv-endosome"], "article_id"=>312341, "categories"=>["Biological Sciences"], "users"=>["Sergi Padilla-Parra", "Mariana Marin", "Naoyuki Kondo", "Gregory B. Melikyan"], "doi"=>["https://dx.doi.org/10.1371/journal.ppat.1002694.t001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Outcomes_of_synchronized_ASLV_endosome_fusion_/312341", "title"=>"Outcomes of synchronized ASLV-endosome fusion.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-05-10 00:39:01"}

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Relative Metric

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