Viral Apoptosis Evasion via the MAPK Pathway by Use of a Host Long Noncoding RNA
An emerging realization of infectious disease is that pathogens can cause a high incidence of genetic instability within the host as a result of infection-induced DNA lesions. These often lead to classical hallmarks of cancer, one of which is the ability to evade apoptosis despite the presence of nu...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-08-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fcimb.2018.00263/full |
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| author | Samantha Barichievy Samantha Barichievy Jerolen Naidoo Jerolen Naidoo Mikaël Boullé Mikaël Boullé Mikaël Boullé Janine Scholefield Suraj P. Parihar Suraj P. Parihar Anna K. Coussens Frank Brombacher Frank Brombacher Alex Sigal Alex Sigal Alex Sigal Musa M. Mhlanga Musa M. Mhlanga Musa M. Mhlanga |
| author_facet | Samantha Barichievy Samantha Barichievy Jerolen Naidoo Jerolen Naidoo Mikaël Boullé Mikaël Boullé Mikaël Boullé Janine Scholefield Suraj P. Parihar Suraj P. Parihar Anna K. Coussens Frank Brombacher Frank Brombacher Alex Sigal Alex Sigal Alex Sigal Musa M. Mhlanga Musa M. Mhlanga Musa M. Mhlanga |
| author_sort | Samantha Barichievy |
| collection | DOAJ |
| description | An emerging realization of infectious disease is that pathogens can cause a high incidence of genetic instability within the host as a result of infection-induced DNA lesions. These often lead to classical hallmarks of cancer, one of which is the ability to evade apoptosis despite the presence of numerous genetic mutations that should be otherwise lethal. The Human Immunodeficiency Virus type 1 (HIV-1) is one such pathogen as it induces apoptosis in CD4+ T cells but is largely non-cytopathic in macrophages. As a consequence there is long-term dissemination of the pathogen specifically by these infected yet surviving host cells. Apoptosis is triggered by double-strand breaks (DSBs), such as those induced by integrating retroviruses like HIV-1, and is coordinated by the p53-regulated long noncoding RNA lincRNA-p21. As is typical for a long noncoding RNA, lincRNA-p21 mediates its activities in a complex with one of its two protein binding partners, namely HuR and hnRNP-K. In this work, we monitor the cellular response to infection to determine how HIV-1 induces DSBs in macrophages yet evades apoptosis in these cells. We show that the virus does so by securing the pro-survival MAP2K1/ERK2 cascade early upon entry, in a gp120-dependent manner, to orchestrate a complex dysregulation of lincRNA-p21. By sequestering the lincRNA-p21 partner HuR in the nucleus, HIV-1 enables lincRNA-p21 degradation. Simultaneously, the virus permits transcription of pro-survival genes by sequestering lincRNA-p21's other protein partner hnRNP-K in the cytoplasm via the MAP2K1/ERK2 pathway. Of particular note, this MAP2K1/ERK2 pro-survival cascade is switched off during T cell maturation and is thus unavailable for similar viral manipulation in mature CD4+ T cells. We show that the introduction of MAP2K1, ERK2, or HDM2 inhibitors in HIV-infected macrophages results in apoptosis, providing strong evidence that the viral-mediated apoptotic block can be released, specifically by restoring the nuclear interaction of lincRNA-p21 and its apoptosis protein partner hnRNP-K. Together, these results reveal a unique example of pathogenic control over mammalian apoptosis and DNA damage via a host long noncoding RNA, and present MAP2K1/ERK2 inhibitors as a novel therapeutic intervention strategy for HIV-1 infection in macrophages. |
| first_indexed | 2024-12-23T03:30:39Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-12-23T03:30:39Z |
| publishDate | 2018-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-44491a2a7efe42fbaddf1e2d9ebe9cba2022-12-21T18:01:43ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882018-08-01810.3389/fcimb.2018.00263380422Viral Apoptosis Evasion via the MAPK Pathway by Use of a Host Long Noncoding RNASamantha Barichievy0Samantha Barichievy1Jerolen Naidoo2Jerolen Naidoo3Mikaël Boullé4Mikaël Boullé5Mikaël Boullé6Janine Scholefield7Suraj P. Parihar8Suraj P. Parihar9Anna K. Coussens10Frank Brombacher11Frank Brombacher12Alex Sigal13Alex Sigal14Alex Sigal15Musa M. Mhlanga16Musa M. Mhlanga17Musa M. Mhlanga18Gene Expression and Biophysics Group, Synthetic Biology ERA, Council for Scientific and Industrial Research (CSIR), Pretoria, South AfricaDiscovery Sciences, IMED Biotech Unit, AstraZeneca AB R&D, Gothenburg, SwedenGene Expression and Biophysics Group, Synthetic Biology ERA, Council for Scientific and Industrial Research (CSIR), Pretoria, South AfricaDivision of Chemical Systems and Synthetic Biology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South AfricaKwaZulu-Natal Research Institute for TB-HIV, Durban, South AfricaUniversity of KwaZulu-Natal, Durban, South AfricaMax Planck Institute for Infection BiologyBerlin, GermanyGene Expression and Biophysics Group, Synthetic Biology ERA, Council for Scientific and Industrial Research (CSIR), Pretoria, South AfricaDivision of Immunology and South African Medical Research Council Immunology of Infectious Diseases, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicinem University of Cape Town, Cape Town, South AfricaInternational Centre for Genetic Engineering and Biotechnology, Cape Town, South AfricaDivision of Medical Microbiology and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South AfricaDivision of Immunology and South African Medical Research Council Immunology of Infectious Diseases, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicinem University of Cape Town, Cape Town, South AfricaInternational Centre for Genetic Engineering and Biotechnology, Cape Town, South AfricaKwaZulu-Natal Research Institute for TB-HIV, Durban, South AfricaUniversity of KwaZulu-Natal, Durban, South AfricaMax Planck Institute for Infection BiologyBerlin, GermanyGene Expression and Biophysics Group, Synthetic Biology ERA, Council for Scientific and Industrial Research (CSIR), Pretoria, South AfricaDivision of Chemical Systems and Synthetic Biology, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Cape Town, South Africa0Gene Expression and Biophysics Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, PortugalAn emerging realization of infectious disease is that pathogens can cause a high incidence of genetic instability within the host as a result of infection-induced DNA lesions. These often lead to classical hallmarks of cancer, one of which is the ability to evade apoptosis despite the presence of numerous genetic mutations that should be otherwise lethal. The Human Immunodeficiency Virus type 1 (HIV-1) is one such pathogen as it induces apoptosis in CD4+ T cells but is largely non-cytopathic in macrophages. As a consequence there is long-term dissemination of the pathogen specifically by these infected yet surviving host cells. Apoptosis is triggered by double-strand breaks (DSBs), such as those induced by integrating retroviruses like HIV-1, and is coordinated by the p53-regulated long noncoding RNA lincRNA-p21. As is typical for a long noncoding RNA, lincRNA-p21 mediates its activities in a complex with one of its two protein binding partners, namely HuR and hnRNP-K. In this work, we monitor the cellular response to infection to determine how HIV-1 induces DSBs in macrophages yet evades apoptosis in these cells. We show that the virus does so by securing the pro-survival MAP2K1/ERK2 cascade early upon entry, in a gp120-dependent manner, to orchestrate a complex dysregulation of lincRNA-p21. By sequestering the lincRNA-p21 partner HuR in the nucleus, HIV-1 enables lincRNA-p21 degradation. Simultaneously, the virus permits transcription of pro-survival genes by sequestering lincRNA-p21's other protein partner hnRNP-K in the cytoplasm via the MAP2K1/ERK2 pathway. Of particular note, this MAP2K1/ERK2 pro-survival cascade is switched off during T cell maturation and is thus unavailable for similar viral manipulation in mature CD4+ T cells. We show that the introduction of MAP2K1, ERK2, or HDM2 inhibitors in HIV-infected macrophages results in apoptosis, providing strong evidence that the viral-mediated apoptotic block can be released, specifically by restoring the nuclear interaction of lincRNA-p21 and its apoptosis protein partner hnRNP-K. Together, these results reveal a unique example of pathogenic control over mammalian apoptosis and DNA damage via a host long noncoding RNA, and present MAP2K1/ERK2 inhibitors as a novel therapeutic intervention strategy for HIV-1 infection in macrophages.https://www.frontiersin.org/article/10.3389/fcimb.2018.00263/fulllincRNA-p21HuRhnRNP-KapoptosisMAP2K1ERK2 |
| spellingShingle | Samantha Barichievy Samantha Barichievy Jerolen Naidoo Jerolen Naidoo Mikaël Boullé Mikaël Boullé Mikaël Boullé Janine Scholefield Suraj P. Parihar Suraj P. Parihar Anna K. Coussens Frank Brombacher Frank Brombacher Alex Sigal Alex Sigal Alex Sigal Musa M. Mhlanga Musa M. Mhlanga Musa M. Mhlanga Viral Apoptosis Evasion via the MAPK Pathway by Use of a Host Long Noncoding RNA Frontiers in Cellular and Infection Microbiology lincRNA-p21 HuR hnRNP-K apoptosis MAP2K1 ERK2 |
| title | Viral Apoptosis Evasion via the MAPK Pathway by Use of a Host Long Noncoding RNA |
| title_full | Viral Apoptosis Evasion via the MAPK Pathway by Use of a Host Long Noncoding RNA |
| title_fullStr | Viral Apoptosis Evasion via the MAPK Pathway by Use of a Host Long Noncoding RNA |
| title_full_unstemmed | Viral Apoptosis Evasion via the MAPK Pathway by Use of a Host Long Noncoding RNA |
| title_short | Viral Apoptosis Evasion via the MAPK Pathway by Use of a Host Long Noncoding RNA |
| title_sort | viral apoptosis evasion via the mapk pathway by use of a host long noncoding rna |
| topic | lincRNA-p21 HuR hnRNP-K apoptosis MAP2K1 ERK2 |
| url | https://www.frontiersin.org/article/10.3389/fcimb.2018.00263/full |
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