Kaposi's sarcoma herpesvirus microRNAs target caspase 3 and regulate apoptosis
Kaposi's sarcoma herpesvirus (KSHV) encodes a cluster of twelve micro (mi)RNAs, which are abundantly expressed during both latent and lytic infection. Previous studies reported that KSHV is able to inhibit apoptosis during latent infection; we thus tested the involvement of viral miRNAs in this...
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| Veröffentlicht in: | PLoS pathogens 2011-12, Vol.7 (12), p.e1002405 |
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| creator | Suffert, Guillaume Malterer, Georg Hausser, Jean Viiliäinen, Johanna Fender, Aurélie Contrant, Maud Ivacevic, Tomi Benes, Vladimir Gros, Frédéric Voinnet, Olivier Zavolan, Mihaela Ojala, Päivi M Haas, Juergen G Pfeffer, Sébastien |
| description | Kaposi's sarcoma herpesvirus (KSHV) encodes a cluster of twelve micro (mi)RNAs, which are abundantly expressed during both latent and lytic infection. Previous studies reported that KSHV is able to inhibit apoptosis during latent infection; we thus tested the involvement of viral miRNAs in this process. We found that both HEK293 epithelial cells and DG75 cells stably expressing KSHV miRNAs were protected from apoptosis. Potential cellular targets that were significantly down-regulated upon KSHV miRNAs expression were identified by microarray profiling. Among them, we validated by luciferase reporter assays, quantitative PCR and western blotting caspase 3 (Casp3), a critical factor for the control of apoptosis. Using site-directed mutagenesis, we found that three KSHV miRNAs, miR-K12-1, 3 and 4-3p, were responsible for the targeting of Casp3. Specific inhibition of these miRNAs in KSHV-infected cells resulted in increased expression levels of endogenous Casp3 and enhanced apoptosis. Altogether, our results suggest that KSHV miRNAs directly participate in the previously reported inhibition of apoptosis by the virus, and are thus likely to play a role in KSHV-induced oncogenesis. |
| doi_str_mv | 10.1371/journal.ppat.1002405 |
| format | Article |
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Previous studies reported that KSHV is able to inhibit apoptosis during latent infection; we thus tested the involvement of viral miRNAs in this process. We found that both HEK293 epithelial cells and DG75 cells stably expressing KSHV miRNAs were protected from apoptosis. Potential cellular targets that were significantly down-regulated upon KSHV miRNAs expression were identified by microarray profiling. Among them, we validated by luciferase reporter assays, quantitative PCR and western blotting caspase 3 (Casp3), a critical factor for the control of apoptosis. Using site-directed mutagenesis, we found that three KSHV miRNAs, miR-K12-1, 3 and 4-3p, were responsible for the targeting of Casp3. Specific inhibition of these miRNAs in KSHV-infected cells resulted in increased expression levels of endogenous Casp3 and enhanced apoptosis. Altogether, our results suggest that KSHV miRNAs directly participate in the previously reported inhibition of apoptosis by the virus, and are thus likely to play a role in KSHV-induced oncogenesis.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1002405</identifier><identifier>PMID: 22174674</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Apoptosis ; Apoptosis - genetics ; Binding sites ; Biochemistry, Molecular Biology ; Biology ; Blotting, Northern ; Blotting, Western ; Cancer ; Caspase 3 - biosynthesis ; Caspase 3 - genetics ; Cell Line ; Down-Regulation ; Gene Expression Regulation, Viral - genetics ; Genomics ; Grants ; Herpesviridae Infections - genetics ; Herpesviridae Infections - metabolism ; Herpesvirus 8, Human - genetics ; Herpesvirus 8, Human - metabolism ; Human health and pathology ; Humans ; In Situ Nick-End Labeling ; Infections ; Infectious diseases ; Kaposis sarcoma ; Life Sciences ; Microbiology and Parasitology ; MicroRNAs - genetics ; Mutagenesis ; Mutagenesis, Site-Directed ; Oligonucleotide Array Sequence Analysis ; Real-Time Polymerase Chain Reaction ; Viral infections ; Virology ; Viruses</subject><ispartof>PLoS pathogens, 2011-12, Vol.7 (12), p.e1002405</ispartof><rights>2011 Suffert et al. 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: Suffert G, Malterer G, Hausser J, Viiliäinen J, Fender A, et al. (2011) Kaposi's Sarcoma Herpesvirus microRNAs Target Caspase 3 and Regulate Apoptosis. 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Altogether, our results suggest that KSHV miRNAs directly participate in the previously reported inhibition of apoptosis by the virus, and are thus likely to play a role in KSHV-induced oncogenesis.</description><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>Binding sites</subject><subject>Biochemistry, Molecular Biology</subject><subject>Biology</subject><subject>Blotting, Northern</subject><subject>Blotting, Western</subject><subject>Cancer</subject><subject>Caspase 3 - biosynthesis</subject><subject>Caspase 3 - genetics</subject><subject>Cell Line</subject><subject>Down-Regulation</subject><subject>Gene Expression Regulation, Viral - genetics</subject><subject>Genomics</subject><subject>Grants</subject><subject>Herpesviridae Infections - genetics</subject><subject>Herpesviridae Infections - metabolism</subject><subject>Herpesvirus 8, Human - genetics</subject><subject>Herpesvirus 8, Human - metabolism</subject><subject>Human health and 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sarcoma herpesvirus microRNAs target caspase 3 and regulate apoptosis</title><author>Suffert, Guillaume ; Malterer, Georg ; Hausser, Jean ; Viiliäinen, Johanna ; Fender, Aurélie ; Contrant, Maud ; Ivacevic, Tomi ; Benes, Vladimir ; Gros, Frédéric ; Voinnet, Olivier ; Zavolan, Mihaela ; Ojala, Päivi M ; Haas, Juergen G ; Pfeffer, Sébastien</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c559t-8eebe7298fe2923691ac1e5a06d73a53c8dd24f7131029c44f5a6d2ba159798f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Apoptosis</topic><topic>Apoptosis - genetics</topic><topic>Binding sites</topic><topic>Biochemistry, Molecular Biology</topic><topic>Biology</topic><topic>Blotting, Northern</topic><topic>Blotting, Western</topic><topic>Cancer</topic><topic>Caspase 3 - biosynthesis</topic><topic>Caspase 3 - genetics</topic><topic>Cell Line</topic><topic>Down-Regulation</topic><topic>Gene 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Previous studies reported that KSHV is able to inhibit apoptosis during latent infection; we thus tested the involvement of viral miRNAs in this process. We found that both HEK293 epithelial cells and DG75 cells stably expressing KSHV miRNAs were protected from apoptosis. Potential cellular targets that were significantly down-regulated upon KSHV miRNAs expression were identified by microarray profiling. Among them, we validated by luciferase reporter assays, quantitative PCR and western blotting caspase 3 (Casp3), a critical factor for the control of apoptosis. Using site-directed mutagenesis, we found that three KSHV miRNAs, miR-K12-1, 3 and 4-3p, were responsible for the targeting of Casp3. Specific inhibition of these miRNAs in KSHV-infected cells resulted in increased expression levels of endogenous Casp3 and enhanced apoptosis. Altogether, our results suggest that KSHV miRNAs directly participate in the previously reported inhibition of apoptosis by the virus, and are thus likely to play a role in KSHV-induced oncogenesis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22174674</pmid><doi>10.1371/journal.ppat.1002405</doi><orcidid>https://orcid.org/0000-0001-6982-9544</orcidid><orcidid>https://orcid.org/0000-0002-8458-348X</orcidid><orcidid>https://orcid.org/0000-0002-6252-4323</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central Open Access; Public Library of Science (PLoS); PubMed Central |
| subjects | Apoptosis Apoptosis - genetics Binding sites Biochemistry, Molecular Biology Biology Blotting, Northern Blotting, Western Cancer Caspase 3 - biosynthesis Caspase 3 - genetics Cell Line Down-Regulation Gene Expression Regulation, Viral - genetics Genomics Grants Herpesviridae Infections - genetics Herpesviridae Infections - metabolism Herpesvirus 8, Human - genetics Herpesvirus 8, Human - metabolism Human health and pathology Humans In Situ Nick-End Labeling Infections Infectious diseases Kaposis sarcoma Life Sciences Microbiology and Parasitology MicroRNAs - genetics Mutagenesis Mutagenesis, Site-Directed Oligonucleotide Array Sequence Analysis Real-Time Polymerase Chain Reaction Viral infections Virology Viruses |
| title | Kaposi's sarcoma herpesvirus microRNAs target caspase 3 and regulate apoptosis |
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