Viral Apoptosis Evasion via the MAPK Pathway by Use of a Host Long Noncoding RNA
| Autor: | Samantha Barichievy, Jerolen Naidoo, Mikaël Boullé, Janine Scholefield, Suraj P. Parihar, Anna K. Coussens, Frank Brombacher, Alex Sigal, Musa M. Mhlanga |
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| Přispěvatelé: | Council for Scientific and Industrial Research [Pretoria] (CSIR), AstraZeneca, Gothenburg, Sweden, University of Cape Town, Africa Health Research Institute [KwaZulu-Natal] (AHRI), University of KwaZulu-Natal (UKZN), Max Planck Institut für Infektionsbiologie (MPIIB), Max-Planck-Gesellschaft, International Centre for Genetic Engineering and Biotechnology [Cape Town] (ICGEB), Universidade de Lisboa (ULISBOA), This research is supported by grant PG V2KYP07 from the Council for Industrial and Scientific Research (CSIR, South Africa) and by a grant from the Emerging Research Area Program & the Centre of Competence Program of The Department of Science and Technology (DST, South Africa) and a grant from the Medical Research Council (South Africa) all to MMM. |
| Rok vydání: | 2018 |
| Předmět: |
MESH: Signal Transduction
0301 basic medicine MAPK/ERK pathway [SDV]Life Sciences [q-bio] MESH: DNA Breaks Double-Stranded lcsh:QR1-502 MAP Kinase Kinase 1 Plasma protein binding HIV Envelope Protein gp120 lcsh:Microbiology ERK2 Heterogeneous-Nuclear Ribonucleoprotein K MESH: HIV-1 MESH: HIV Envelope Protein gp120 chemistry.chemical_compound Cellular and Infection Microbiology 0302 clinical medicine Transcription (biology) MAP2K1 DNA Breaks Double-Stranded MESH: Immune Evasion Cells Cultured Original Research Mitogen-Activated Protein Kinase 1 0303 health sciences apoptosis Long non-coding RNA 3. Good health Cell biology MESH: RNA Long Noncoding Infectious Diseases medicine.anatomical_structure 030220 oncology & carcinogenesis Host-Pathogen Interactions HuR RNA Long Noncoding MESH: MAP Kinase Kinase 1 Signal Transduction MESH: Cells Cultured MESH: Mitogen-Activated Protein Kinase 1 Cyclin-Dependent Kinase Inhibitor p21 Nutlin3a Microbiology (medical) DNA damage T cell Immunology macrophage Biology Microbiology Virus MESH: Cyclin-Dependent Kinase Inhibitor p21 03 medical and health sciences hnRNP-K MESH: Heterogeneous-Nuclear Ribonucleoprotein K medicine Humans lincRNA-p21 Gene Immune Evasion 030304 developmental biology MESH: Humans Macrophages MESH: Apoptosis MESH: Host-Pathogen Interactions MESH: Macrophages 030104 developmental biology chemistry Apoptosis HIV-1 Function (biology) DNA |
| Zdroj: | Frontiers in Cellular and Infection Microbiology Frontiers in Cellular and Infection Microbiology, Frontiers, 2018, 8, pp.263. ⟨10.3389/fcimb.2018.00263⟩ Frontiers in Cellular and Infection Microbiology, Vol 8 (2018) |
| ISSN: | 2235-2988 |
| DOI: | 10.3389/fcimb.2018.00263 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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