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{"title"=>"Cholesterol Dependence of Collagen and Echovirus 1 Trafficking along the Novel α2β1 Integrin Internalization Pathway", "type"=>"journal", "authors"=>[{"first_name"=>"Elina", "last_name"=>"Siljamäki", "scopus_author_id"=>"55180703200"}, {"first_name"=>"Nina", "last_name"=>"Rintanen", "scopus_author_id"=>"25936784700"}, {"first_name"=>"Maija", "last_name"=>"Kirsi", "scopus_author_id"=>"55583766400"}, {"first_name"=>"Paula", "last_name"=>"Upla", "scopus_author_id"=>"6507257048"}, {"first_name"=>"Wei", "last_name"=>"Wang", "scopus_author_id"=>"57192619234"}, {"first_name"=>"Mikko", "last_name"=>"Karjalainen", "scopus_author_id"=>"57197672793"}, {"first_name"=>"Elina", "last_name"=>"Ikonen", "scopus_author_id"=>"35384210100"}, {"first_name"=>"Varpu", "last_name"=>"Marjomäki", "scopus_author_id"=>"6603691589"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"doi"=>"10.1371/journal.pone.0055465", "sgr"=>"84873494065", "issn"=>"19326203", "pui"=>"368294444", "isbn"=>"1932-6203 (Electronic)\\n1932-6203 (Linking)", "pmid"=>"23393580", "scopus"=>"2-s2.0-84873494065"}, "id"=>"de116168-ca0e-3160-810e-73dd85f75aaa", "abstract"=>"We have previously shown that soluble collagen and a human pathogen, echovirus 1 (EV1) cluster α2β1 integrin on the plasma membrane and cause their internalization into cytoplasmic endosomes. Here we show that cholesterol plays a major role not only in the uptake of α2β1 integrin and its ligands but also in the formation of α2 integrin-specific multivesicular bodies (α2-MVBs) and virus infection. EV1 infection and α2β1 integrin internalization were totally halted by low amounts of the cholesterol-aggregating drugs filipin or nystatin. Inhibition of cholesterol synthesis and accumulation of lanosterol after ketoconazole treatment inhibited uptake of collagen, virus and clustered integrin, and prevented formation of multivesicular bodies and virus infection. Loading of lipid starved cells with cholesterol increased infection to some extent but could not completely restore EV1 infection to control levels. Cold Triton X-100 treatment did not solubilize the α2-MVBs suggesting, together with cholesterol labeling, that the cytoplasmic endosomes were enriched in detergent-resistant lipids in contrast to αV integrin labeled control endosomes in the clathrin pathway. Cholesterol aggregation leading to increased ion permeability caused a significant reduction in EV1 uncoating in endosomes as judged by sucrose gradient centrifugation and by neutral red-based uncoating assay. In contrast, the replication step was not dependent on cholesterol in contrast to the reports on several other viruses. In conclusion, our results showed that the integrin internalization pathway is dependent on cholesterol for uptake of collagen, EV1 and integrin, for maturation of endosomal structures and for promoting EV1 uncoating. The results thus provide novel information for developing anti-viral strategies and more insight into collagen and integrin trafficking.", "link"=>"http://www.mendeley.com/research/cholesterol-dependence-collagen-echovirus-1-trafficking-along-novel-%CE%B12%CE%B21-integrin-internalization-pa", "reader_count"=>17, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Librarian"=>1, "Researcher"=>4, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Librarian"=>1, "Researcher"=>4, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>6, "Student > Postgraduate"=>1, "Student > Bachelor"=>1, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>8, "Medicine and Dentistry"=>3, "Physics and Astronomy"=>1, "Chemistry"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Chemistry"=>{"Chemistry"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>8}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Finland"=>1, "United Kingdom"=>1}, "group_count"=>1}

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• http://doi.org/10.1038/cdd.2015.67
• http://doi.org/10.3390/v7122945
• http://doi.org/10.1038/srep23110
• http://doi.org/10.3389/fmicb.2020.01817
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• http://doi.org/10.1016/j.actbio.2017.08.038
• http://doi.org/10.1111/cmi.12425
• http://doi.org/10.1128/JVI.00342-16

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Figshare

• {"files"=>["https://ndownloader.figshare.com/files/482511", "https://ndownloader.figshare.com/files/482516", "https://ndownloader.figshare.com/files/482526", "https://ndownloader.figshare.com/files/482528"], "description"=>"<div><p>We have previously shown that soluble collagen and a human pathogen, echovirus 1 (EV1) cluster α2β1 integrin on the plasma membrane and cause their internalization into cytoplasmic endosomes. Here we show that cholesterol plays a major role not only in the uptake of α2β1 integrin and its ligands but also in the formation of α2 integrin-specific multivesicular bodies (α2-MVBs) and virus infection. EV1 infection and α2β1 integrin internalization were totally halted by low amounts of the cholesterol-aggregating drugs filipin or nystatin. Inhibition of cholesterol synthesis and accumulation of lanosterol after ketoconazole treatment inhibited uptake of collagen, virus and clustered integrin, and prevented formation of multivesicular bodies and virus infection. Loading of lipid starved cells with cholesterol increased infection to some extent but could not completely restore EV1 infection to control levels. Cold Triton X-100 treatment did not solubilize the α2-MVBs suggesting, together with cholesterol labeling, that the cytoplasmic endosomes were enriched in detergent-resistant lipids in contrast to αV integrin labeled control endosomes in the clathrin pathway. Cholesterol aggregation leading to increased ion permeability caused a significant reduction in EV1 uncoating in endosomes as judged by sucrose gradient centrifugation and by neutral red-based uncoating assay. In contrast, the replication step was not dependent on cholesterol in contrast to the reports on several other viruses. In conclusion, our results showed that the integrin internalization pathway is dependent on cholesterol for uptake of collagen, EV1 and integrin, for maturation of endosomal structures and for promoting EV1 uncoating. The results thus provide novel information for developing anti-viral strategies and more insight into collagen and integrin trafficking.</p> </div>", "links"=>[], "tags"=>["dependence", "collagen", "echovirus", "trafficking", "integrin", "internalization", "pathway"], "article_id"=>155841, "categories"=>["Virology", "Biochemistry", "Cell Biology"], "users"=>["Elina Siljamäki", "Nina Rintanen", "Maija Kirsi", "Paula Upla", "Wei Wang", "Mikko Karjalainen", "Elina Ikonen", "Varpu Marjomäki"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0055465.s001", "https://dx.doi.org/10.1371/journal.pone.0055465.s002", "https://dx.doi.org/10.1371/journal.pone.0055465.s003", "https://dx.doi.org/10.1371/journal.pone.0055465.s004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Cholesterol_Dependence_of_Collagen_and_Echovirus_1_Trafficking_along_the_Novel_2_1_Integrin_Internalization_Pathway__/155841", "title"=>"Cholesterol Dependence of Collagen and Echovirus 1 Trafficking along the Novel α2β1 Integrin Internalization Pathway", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-02-05 01:37:21"}
• {"files"=>["https://ndownloader.figshare.com/files/494748"], "description"=>"<p>A) Differential staining of the internalized (green) and surface-bound (red or yellow) α2β1 integrin 2 h after internalization. Nystatin (50 µg/ml), filipin (1 µg/ml) or equal amount of DMSO (control) were used. Bars, 10 µm. The ratio of surface versus internalized α2β1 integrin was determined using the internalization algorithm in BioImageXD software and the higher ratio means lower amount of internalization. Results are expressed as mean values measured from 30 cells from 3 independent experiments ± standard error (SE). ***P<0.001. B) The effect of nystatin (50 µg/ml) or filipin (1 µg/ml) on EV1 infectivity was determined. Results are expressed as mean values from three independent experiments ± SE (more than 400 cells counted). ***P<0.001. The EV1 capsid proteins were visualized after 7 h p.i. Bars, 10 µm.</p>", "links"=>[], "tags"=>["sequestering", "drugs", "inhibit", "integrin", "internalization", "ev1"], "article_id"=>165256, "categories"=>["Virology", "Biochemistry", "Cell Biology"], "users"=>["Elina Siljamäki", "Nina Rintanen", "Maija Kirsi", "Paula Upla", "Wei Wang", "Mikko Karjalainen", "Elina Ikonen", "Varpu Marjomäki"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0055465.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cholesterol_sequestering_drugs_inhibit_945_2_946_1_integrin_internalization_and_EV1_infection_/165256", "title"=>"Cholesterol sequestering drugs inhibit α2β1 integrin internalization and EV1 infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-05 01:27:36"}
• {"files"=>["https://ndownloader.figshare.com/files/494899"], "description"=>"<p>A) Thin layer chromatography analysis of sterols in SAOS-α2β1 cells. B) Representative pictures of internalization of α2 integrin after ketoconazole, 5% LPDS or 10% FCS treatments. Internalized integrin is seen as green labeling and surface-bound integrin as red or yellow dye. The ratio of voxels between surface and internalized integrin was quantified with internalization algorithm embedded in BioImageXD software. Higher ratio means higher amount of integrin in plasma membrane. Results are averages from together 33 cells from 3 independent tests+SE. C) Electron microscopic example images of integrin structures after antibody clustering in 5% LPDS+ketoconazole cells at 0.5 and 3.5 h time points. D) Proportional change of EV1 infectivity in cells treated with 10% FCS DMEM, 5% LDPS DMEM or 5% LPDS DMEM with ketoconazole. Results are averages of four independent tests (+SE). **P<0.05, ***P<0.001. E) EV1 infectivity in cells treated with 10% FCS DMEM, 5% LDPS DMEM or 5% LPDS+mβCD-cholesterol. Results are averages of three independent tests (+SE), together over 750 cells were counted. F) The effect of U18666A (3 µg/ml) on EV1 infection percentage. EV1 infectivity was calculated together from 750 cells from three individual tests (+SE). Cholesterol labeling with filipin and lysosomal labeling with Lamp-1 was performed to confirm the efficacy of the drug. Bars 10 µm.</p>", "links"=>[], "tags"=>["synthesis", "disrupts", "integrin", "internalization", "ev1"], "article_id"=>165411, "categories"=>["Virology", "Biochemistry", "Cell Biology"], "users"=>["Elina Siljamäki", "Nina Rintanen", "Maija Kirsi", "Paula Upla", "Wei Wang", "Mikko Karjalainen", "Elina Ikonen", "Varpu Marjomäki"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0055465.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_cholesterol_synthesis_disrupts_integrin_internalization_and_EV1_infection_/165411", "title"=>"Inhibition of cholesterol synthesis disrupts integrin internalization and EV1 infection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-05 01:30:11"}
• {"files"=>["https://ndownloader.figshare.com/files/495043"], "description"=>"<p>A) Percentage of cells showing internalized collagen vesicles vs. cell surface-enriched collagen was counted from 77 to 80 cells cultivated in 10% DMEM or 5% LPDS DMEM with ketoconazole, respectively. Typical images used in calculations are shown. Bars 10 µm. B) Ratio of cell surface-enriched vs. internalized collagen was calculated from confocal sections from 20 cells cultivated for 6 h in 10% DMEM, 5% LPDS or 5% LPDS with ketoconazole. Surface-labeled collagen is seen as green or yellow and internalized collagen as red staining. Representative images are shown. Higher ratio means higher collagen label at plasma membrane. Results are mean values from together 20 cells of 2 independent tests (+ SE). Bars 10 µm.</p>", "links"=>[], "tags"=>["uptake", "disturbed", "ketoconazole"], "article_id"=>165545, "categories"=>["Virology", "Biochemistry", "Cell Biology"], "users"=>["Elina Siljamäki", "Nina Rintanen", "Maija Kirsi", "Paula Upla", "Wei Wang", "Mikko Karjalainen", "Elina Ikonen", "Varpu Marjomäki"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0055465.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Collagen_uptake_is_disturbed_by_ketoconazole_treatment_/165545", "title"=>"Collagen uptake is disturbed by ketoconazole treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-05 01:32:25"}
• {"files"=>["https://ndownloader.figshare.com/files/495203"], "description"=>"<p>Representative images of cells showing α2 integrin (red) and collagen (green) labeling, 2 or 6 h after plating cells on soluble collagen with or without ketoconazole. Bars 10 µm.</p>", "links"=>[], "tags"=>["integrin"], "article_id"=>165717, "categories"=>["Virology", "Biochemistry", "Cell Biology"], "users"=>["Elina Siljamäki", "Nina Rintanen", "Maija Kirsi", "Paula Upla", "Wei Wang", "Mikko Karjalainen", "Elina Ikonen", "Varpu Marjomäki"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0055465.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Colocalization_of_945_2_integrin_with_collagen_/165717", "title"=>"Colocalization of α2 integrin with collagen.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-05 01:35:17"}
• {"files"=>["https://ndownloader.figshare.com/files/495363"], "description"=>"<p>A) Confocal images of control cells and cells treated with Triton X-100 or filipin 2 h after clustering and internalization. Bars, 10 µm.B) The average amount of structures positive for α2 or αV integrin per cell. C) The sum of average fluorescence intensities of structures positive for α2 or αV integrin. D) The average volume of α2 or αV integrin-positive structures per cell. B–D) The results were quantified with the segmentation tool in the BioImageXD software. ***P<0.005, **P<0.001, *P<0.01. Results are expressed as mean values measured from z-stacks of 15 cells ± SE. E) Representative confocal image of EV1 infected cell at 4 h p.i. labeled with filipin (blue), anti-dsRNA (green) and anti-VP1 (red) antibodies. Illustrative examples of filipin and VP1 colocalizing structures are marked with arrowheads. Bar 10 µm.</p>", "links"=>[], "tags"=>["integrin", "structures", "lipid"], "article_id"=>165880, "categories"=>["Virology", "Biochemistry", "Cell Biology"], "users"=>["Elina Siljamäki", "Nina Rintanen", "Maija Kirsi", "Paula Upla", "Wei Wang", "Mikko Karjalainen", "Elina Ikonen", "Varpu Marjomäki"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0055465.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_945_2_integrin_structures_contain_lipid_microdomains_/165880", "title"=>"α2 integrin structures contain lipid microdomains.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-05 01:38:00"}
• {"files"=>["https://ndownloader.figshare.com/files/495490"], "description"=>"<p>A) EV1 infectivity of control cells and cells treated with filipin and nystatin after 5 min p.i. (P<0.001, binomial <i>t</i>-test). Confocal images show labeled EV1 capsid proteins at 7 h p.i. Bars, 10 µm. B) EV1 infection percentage of cells treated with nystatin or filipin that were added at different time points p.i. The results are mean values of 3 independent experiments ± SE (more than 700 cells counted). C) Infection percentage of neutral-red labeled EV1 (NR-EV1) with light treatments in different times p.i. The control cells were not exposed to light reaction. Results are averages of 2 independent tests (+ SE) and over 800 cells were counted at the minimum. D) Sucrose gradient sedimentation assay of uncoating with [³⁵S]methionine-labeled EV1 at 4 h p.i. RNA containing virus sediments at 160S, whereas the 80S represents empty capsids from which the viral RNA genome is released. E-F) As in D except filipin or nystatin was added to the cells 15 min p.i. G) Cointernalized Fluospheres and clustered α2 integrin colocalize in endosomes. Total intensity of FluoSpheres in endosomes was analysed from confocal sections by using the intensity algorithm in BioImageXD. Together 20 cells from 2 separate tests were analysed (+ SE). *P<0.01. Bars, 10 µm.</p>", "links"=>[], "tags"=>["aggregating", "drugs", "ev1"], "article_id"=>166011, "categories"=>["Virology", "Biochemistry", "Cell Biology"], "users"=>["Elina Siljamäki", "Nina Rintanen", "Maija Kirsi", "Paula Upla", "Wei Wang", "Mikko Karjalainen", "Elina Ikonen", "Varpu Marjomäki"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0055465.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_effects_of_cholesterol_aggregating_drugs_on_EV1_uncoating_/166011", "title"=>"The effects of cholesterol aggregating drugs on EV1 uncoating.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-05 01:40:11"}
• {"files"=>["https://ndownloader.figshare.com/files/495586"], "description"=>"<p>EV1 or antibody clustering triggers integrin internalization via macropinocytosis and leads to formation of multivesicular structures that are distinct from clathrin-dependent internalization and conventional acidic endosomes and lysosomes <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055465#pone.0055465-Upla1\" target=\"_blank\">[10]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055465#pone.0055465-Rintanen1\" target=\"_blank\">[14]</a>, <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055465#pone.0055465-Karjalainen2\" target=\"_blank\">[15]</a>. Pertubation of cholesterol with filipin, nystatin or ketoconazole inhibited internalization of α2 integrin and its ligands. Furthermore, the maturation of α2-MVBs was also prevented after cholesterol depletion. α2 integrin structures were found to be rich in cholesterol based on several criteria: 1) cholesterol sequestering drugs inhibited the viral uncoating inside the endosomes, 2) α2-MVBs were resistant for Triton X-100 treatment and sensitive for filipin in contrast to αV integrin structures, and 3) EV1 containing structures were filipin positive. Moreover, EV1 infection was insensitive for U18666A whereas the compound interferes with trafficking from classical late endosomes and lysosomes. Abbreviations used: α2-MVB, α2 integrin containing multivesicular bodies; cav-1, caveolin-1; CI-MPR, cation-independent mannose-phosphate receptor; Dil-LDL, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanina-labeled LDL; EEA1, early endosomal antigen 1; EGFR, epidermal growth factor receptor; EV1, echovirus 1; Lamp-1, Lysosomal-associated membrane protein-1; Tf, transferrin; TX-100, Triton X-100; U18666A, 3-β-[2-(diethylamino)ethoxy]androst-5-en-17-one.</p>", "links"=>[], "tags"=>["non-acidic", "integrin", "clustering-triggered", "acidic", "clathrin-dependent"], "article_id"=>166098, "categories"=>["Virology", "Biochemistry", "Cell Biology"], "users"=>["Elina Siljamäki", "Nina Rintanen", "Maija Kirsi", "Paula Upla", "Wei Wang", "Mikko Karjalainen", "Elina Ikonen", "Varpu Marjomäki"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0055465.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_the_non_acidic_945_2_integrin_clustering_triggered_and_the_acidic_clathrin_dependent_pathways_/166098", "title"=>"Summary of the non-acidic α2 integrin clustering-triggered and the acidic clathrin-dependent pathways.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-05 01:41:38"}

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Relative Metric

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F1000Prime