The tumor suppressor protein PML controls apoptosis induced by the HIV-1 envelope
| Autor: | J-L, Perfettini, R, Nardacci, C, Séror, M, Bourouba, F, Subra, L, Gros, G, Manic, A, Amendola, P, Masdehors, F, Rosselli, D M, Ojcius, C, Auclair, H, de Thé, M-L, Gougeon, M, Piacentini, G, Kroemer |
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| Rok vydání: | 2008 |
| Předmět: |
Programmed cell death
viruses Apoptosis Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Promyelocytic Leukemia Protein Protein Serine-Threonine Kinases Giant Cells Promyelocytic leukemia protein Glycoprotein complex Humans RNA Small Interfering Nuclear protein Molecular Biology Transcription factor Protein PML Syncytium biology Tumor Suppressor Proteins env Gene Products Human Immunodeficiency Virus Nuclear Proteins virus diseases Cell Biology Cell biology DNA-Binding Proteins HIV-1 biology.protein Tumor Suppressor Protein p53 HeLa Cells Signal Transduction Transcription Factors |
| Zdroj: | Cell Death & Differentiation. 16:298-311 |
| ISSN: | 1476-5403 1350-9047 |
| DOI: | 10.1038/cdd.2008.158 |
| Popis: | Promyelomonocytic leukemia (PML) is a prominent oncosuppressor whose inactivation is involved in the pathogenesis of hematological and epithelial cancers. Here, we report that PML aggregated in nuclear bodies in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. PML aggregation occurred after the fusion of nuclei (karyogamy) within syncytia but before the apoptotic program was activated. The aggregation of PML was detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Using a range of specific inhibitors of PML (the oncogenic PML/RARalpha fusion product or specific small interfering RNAs), we demonstrated that, in Env-elicited syncytia, PML was required for activating phosphorylation of ataxia telangiectasia mutated (ATM), which colocalized with PML in nuclear bodies, in a molecular complex that also involved topoisomerase IIbeta-binding protein 1. PML knockdown thus inhibited the ATM-dependent DNA damage response that culminates in the activation of p53, p53-dependent transcription of pro-apoptotic genes and cell death. Infection of CD4-expressing cells with HIV-1 also induced syncytial apoptosis, which could be suppressed by inhibiting PML. Altogether, these data indicate that PML activation is a critical early event that participates in the apoptotic demise of HIV-1-elicited syncytia. |
| Databáze: | OpenAIRE |
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