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

Critical involvement of the ATM-dependent DNA damage response in the apoptotic demise of HIV-1-elicited syncytia. - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

* Corresponding author 1 U848 - Apoptose, cancer et immunité 2 Laboratory of Cell Biology 3 LBPA - Laboratoire de Biologie et de Pharmacologie Appliquée 4 GC FRE2939 - Génomes et cancer 5 Immunité Antivirale, Biothérapie et Vaccins 6 Faculty of Medicine 7 Department of Biopathology and Diagnosing Imaging 8 School of Natural Sciences 9 Department of Immunology 10 Imunología, Facultad de Medicina 11 PVM - Pathologie et virologie moléculaire 12 Department of Biology

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.

Autor: Jean-Luc Perfettini - Roberta Nardacci - Mehdi Bourouba - Frédéric Subra - Laurent Gros - Claire Séror - Gwenola Manic - Filip



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