TY - JOUR
T1 - Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia
AU - Perfettini, Jean Luc
AU - Nardacci, Roberta
AU - Bourouba, Mehdi
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
PY - 2008/6/18
Y1 - 2008/6/18
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=49349092475&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0002458
DO - 10.1371/journal.pone.0002458
M3 - 文章
C2 - 18560558
AN - SCOPUS:49349092475
SN - 1932-6203
VL - 3
JO - PLoS ONE
JF - PLoS ONE
IS - 6
M1 - e2458
ER -
