Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia.
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...
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2008
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oai:doaj.org-article:15997d8a8c2b4aaeb617c9750ec6c13c2021-11-25T06:12:01ZCritical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia.1932-620310.1371/journal.pone.0002458https://doaj.org/article/15997d8a8c2b4aaeb617c9750ec6c13c2008-06-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/18560558/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203DNA 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.Jean-Luc PerfettiniRoberta NardacciMehdi BouroubaFrédéric SubraLaurent GrosClaire SérorGwenola ManicFilippo RosselliAlessandra AmendolaPeggy MasdehorsLuciana ChessaGiuseppe NovelliDavid M OjciusJan Konrad SiwickiMagdalena ChechlinskaChristian AuclairJosé R RegueiroHugues de ThéMarie-Lise GougeonMauro PiacentiniGuido KroemerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 3, Iss 6, p e2458 (2008) |
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Medicine R Science Q 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 Piacentini Guido Kroemer Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. |
| description |
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. |
| format |
article |
| author |
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 Piacentini Guido Kroemer |
| author_facet |
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 Piacentini Guido Kroemer |
| author_sort |
Jean-Luc Perfettini |
| title |
Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. |
| title_short |
Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. |
| title_full |
Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. |
| title_fullStr |
Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. |
| title_full_unstemmed |
Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. |
| title_sort |
critical involvement of the atm-dependent dna damage response in the apoptotic demise of hiv-1-elicited syncytia. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2008 |
| url |
https://doaj.org/article/15997d8a8c2b4aaeb617c9750ec6c13c |
| work_keys_str_mv |
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