The tumor suppressor protein PML controls apoptosis induced by the HIV-1 envelope

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

Research output: Contribution to journalArticlepeer-review

Abstract

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/RARα 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 IIβ-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.

Original languageEnglish
Pages (from-to)298-311
Number of pages14
JournalCell Death and Differentiation
Volume16
Issue number2
DOIs
Publication statusPublished - 2009

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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