Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia

Jean Luc Perfettini, Roberta Nardacci, Mehdi Bourouba, Frédéric Subra, Laurent Gros, Claire Séror, Gwenola Manic, Filippo Rosselli, Alessandra Amendola, Peggy Masdehors, Luciana Chessa, Giuseppe Novelli, David M. Ojcius, Jan Konrad Siwicki, Magdalena Chechlinska, Christian Auclair, José R. Regueiro, Hugues de Thé, Marie Lise Gougeon, Mauro PiacentiniGuido Kroemer

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

DNA damage can activate the oncosuppressor protein ataxia telangiectasia mutated (ATM), which phosphorylates the histone H2AX within characteristic DNA damage foci. Here, we show that ATM undergoes an activating phosphorylation in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. This was accompanied by aggregation of ATM in discrete nuclear foci that also contained phospho-histone H2AX. DNA damage foci containing phosphorylated ATM and H2AX were 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. Knockdown of ATM or of its obligate activating factor NBS1 (Nijmegen breakage syndrome 1 protein), as well as pharmacological inhibition of ATM with KU-55933, inhibited H2AX phosphorylation and prevented Env-elicited syncytia from undergoing apoptosis. ATM was found indispensable for the activation of MAP kinase p38, which catalyzes the activating phosphorylation of p53 on serine 46, thereby causing p53 dependent apoptosis. Both wild type HIV-1 and an HIV-1 mutant lacking integrase activity induced syncytial apoptosis, which could be suppressed by inhibiting ATM. HIV-1-infected T lymphoblasts from patients with inactivating ATM or NBS1 mutations also exhibited reduced syncytial apoptosis. Altogether these results indicate that apoptosis induced by a fusogenic HIV-1 Env follows a pro-apoptotic pathway involving the sequential activation of ATM, p38MAPK and p53.

Original languageEnglish
Article numbere2458
JournalPLoS One
Volume3
Issue number6
DOIs
Publication statusPublished - Jun 18 2008

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Ataxia Telangiectasia
giant cells
Giant Cells
Human immunodeficiency virus 1
Viruses
DNA damage
DNA Damage
HIV-1
apoptosis
Phosphorylation
Apoptosis
DNA
phosphorylation
Nijmegen Breakage Syndrome
histones
Histones
Ataxia Telangiectasia Mutated Proteins
Chemical activation
Integrases
proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. / Perfettini, Jean Luc; Nardacci, Roberta; Bourouba, Mehdi; Subra, Frédéric; Gros, Laurent; Séror, Claire; Manic, Gwenola; Rosselli, Filippo; Amendola, Alessandra; Masdehors, Peggy; Chessa, Luciana; Novelli, Giuseppe; Ojcius, David M.; Siwicki, Jan Konrad; Chechlinska, Magdalena; Auclair, Christian; Regueiro, José R.; de Thé, Hugues; Gougeon, Marie Lise; Piacentini, Mauro; Kroemer, Guido.

In: PLoS One, Vol. 3, No. 6, e2458, 18.06.2008.

Research output: Contribution to journalArticle

Perfettini, JL, Nardacci, R, Bourouba, M, Subra, F, Gros, L, Séror, C, Manic, G, Rosselli, F, Amendola, A, Masdehors, P, Chessa, L, Novelli, G, Ojcius, DM, Siwicki, JK, Chechlinska, M, Auclair, C, Regueiro, JR, de Thé, H, Gougeon, ML, Piacentini, M & Kroemer, G 2008, 'Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia', PLoS One, vol. 3, no. 6, e2458. https://doi.org/10.1371/journal.pone.0002458
Perfettini, Jean Luc ; Nardacci, Roberta ; Bourouba, Mehdi ; Subra, Frédéric ; Gros, Laurent ; Séror, Claire ; Manic, Gwenola ; Rosselli, Filippo ; Amendola, Alessandra ; Masdehors, Peggy ; Chessa, Luciana ; Novelli, Giuseppe ; Ojcius, David M. ; Siwicki, Jan Konrad ; Chechlinska, Magdalena ; Auclair, Christian ; Regueiro, José R. ; de Thé, Hugues ; Gougeon, Marie Lise ; Piacentini, Mauro ; Kroemer, Guido. / Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. In: PLoS One. 2008 ; Vol. 3, No. 6.
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AU - Subra, Frédéric

AU - Gros, Laurent

AU - Séror, Claire

AU - Manic, Gwenola

AU - Rosselli, Filippo

AU - Amendola, Alessandra

AU - Masdehors, Peggy

AU - Chessa, Luciana

AU - Novelli, Giuseppe

AU - Ojcius, David M.

AU - Siwicki, Jan Konrad

AU - Chechlinska, Magdalena

AU - Auclair, Christian

AU - Regueiro, José R.

AU - de Thé, Hugues

AU - Gougeon, Marie Lise

AU - Piacentini, Mauro

AU - Kroemer, Guido

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N2 - DNA damage can activate the oncosuppressor protein ataxia telangiectasia mutated (ATM), which phosphorylates the histone H2AX within characteristic DNA damage foci. Here, we show that ATM undergoes an activating phosphorylation in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. This was accompanied by aggregation of ATM in discrete nuclear foci that also contained phospho-histone H2AX. DNA damage foci containing phosphorylated ATM and H2AX were 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. Knockdown of ATM or of its obligate activating factor NBS1 (Nijmegen breakage syndrome 1 protein), as well as pharmacological inhibition of ATM with KU-55933, inhibited H2AX phosphorylation and prevented Env-elicited syncytia from undergoing apoptosis. ATM was found indispensable for the activation of MAP kinase p38, which catalyzes the activating phosphorylation of p53 on serine 46, thereby causing p53 dependent apoptosis. Both wild type HIV-1 and an HIV-1 mutant lacking integrase activity induced syncytial apoptosis, which could be suppressed by inhibiting ATM. HIV-1-infected T lymphoblasts from patients with inactivating ATM or NBS1 mutations also exhibited reduced syncytial apoptosis. Altogether these results indicate that apoptosis induced by a fusogenic HIV-1 Env follows a pro-apoptotic pathway involving the sequential activation of ATM, p38MAPK and p53.

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