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. © 2008 Perfettini et al.

Perfettini, J.l., Nardacci, R., Bourouba, M., Subra, F., Gros, L., Seror, C., et al. (2008). Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. PLOS ONE, 3(6), e2458 [10.1371/journal.pone.0002458].

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

NOVELLI, GIUSEPPE;PIACENTINI, MAURO;
2008-01-01

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. © 2008 Perfettini et al.
2008
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/03 - GENETICA MEDICA
English
Con Impact Factor ISI
2 morpholino 6 (1 thianthrenyl) 4 pyranone; ATM protein; CD4 antigen; DNA; histone H2AX; integrase; mitogen activated protein kinase p38; nibrin; protein p53; serine; tumor suppressor protein; virus envelope protein; cell cycle protein; DNA binding protein; histone; protein serine threonine kinase; adult; apoptosis; article; brain tissue; catalysis; CD4+ T lymphocyte; controlled study; correlation analysis; DNA damage; enzyme activation; enzyme activity; gene mutation; human; human cell; Human immunodeficiency virus 1 infection; human tissue; in vitro study; in vivo study; leukocyte; lymph node; male; protein aggregation; protein phosphorylation; signal transduction; syncytium; female; giant cell; HeLa cell; Human immunodeficiency virus 1; immunohistochemistry; metabolism; phosphorylation; physiology; RNA interference; virology; Ataxia telangiectasia; Human immunodeficiency virus 1; Adult; Apoptosis; Cell Cycle Proteins; DNA Damage; DNA-Binding Proteins; Female; Giant Cells; Hela Cells; Histones; HIV-1; Humans; Immunohistochemistry; Male; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Protein-Serine-Threonine Kinases; RNA Interference; Tumor Suppressor Protein p53; Tumor Suppressor Proteins
Perfettini, J.l., Nardacci, R., Bourouba, M., Subra, F., Gros, L., Seror, C., et al. (2008). Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. PLOS ONE, 3(6), e2458 [10.1371/journal.pone.0002458].
Perfettini, Jl; Nardacci, R; Bourouba, M; Subra, F; Gros, L; Seror, C; Manic, G; Rosselli, F; Amendola, A; Masdehors, P; Chessa, L; Novelli, G; Ojcius, Dm; Siwicki, Jk; Chechlinska, M; Auclair, C; Regueiro, Jr; de The, H; Gougeon, Ml; Piacentini, M; Kroemer, G
Articolo su rivista
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/30247
Citazioni
  • ???jsp.display-item.citation.pmc??? 19
  • Scopus 36
  • ???jsp.display-item.citation.isi??? 34
social impact