Sequential involvement of Cdk1, mTOR and p53 in apoptosis induced by the HIV-1 envelope
M. Castedo
(1, 2)
,
Thomas Roumier
(2, 1)
,
Julià Blanco
(3)
,
Karine Ferri
(2, 1)
,
Jordi Barretina
(3)
,
Lionel Tintignac
(2, 1)
,
Karine Andreau
(2, 1)
,
Jean-Luc Perfettini
(2, 1)
,
Alessandra Amendola
(4)
,
Roberta Nardacci
(4)
,
Philippe Leduc
(5)
,
Donald E Ingber
(5)
,
Sabine Druillennec
(6)
,
Bernard Roques
(6)
,
Serge A. Leibovitch
(2, 1)
,
Montserrat Vilella-Bach
(7)
,
Jie Chen
(7)
,
José A.Este
(3)
,
Nazanine Modjtahedi
(2, 1)
,
Mauro Piacentini
(4, 8)
,
Guido Kroemer
(2, 1)
1
IGR -
Institut Gustave Roussy
2 Génétique oncologique [Villejuif]
3 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
4 Istituto nazionale per le malattie infettive "L. Spallanzani"
5 HMS - Harvard Medical School [Boston]
6 Pharmacochimie moléculaire et structurale
7 UIUC - University of Illinois at Urbana-Champaign [Urbana]
8 Università degli Studi di Roma Tor Vergata [Roma] = University of Rome Tor Vergata
2 Génétique oncologique [Villejuif]
3 UAB - Universitat Autònoma de Barcelona = Autonomous University of Barcelona = Universidad Autónoma de Barcelona
4 Istituto nazionale per le malattie infettive "L. Spallanzani"
5 HMS - Harvard Medical School [Boston]
6 Pharmacochimie moléculaire et structurale
7 UIUC - University of Illinois at Urbana-Champaign [Urbana]
8 Università degli Studi di Roma Tor Vergata [Roma] = University of Rome Tor Vergata
Lionel Tintignac
- Fonction : Auteur
- PersonId : 1206019
- ORCID : 0000-0001-5902-1138
Jean-Luc Perfettini
- Fonction : Auteur
- PersonId : 1298859
- IdHAL : jean-luc-perfettini
- ORCID : 0000-0002-2427-2604
- IdRef : 07448897X
Nazanine Modjtahedi
- Fonction : Auteur
- PersonId : 741378
- IdHAL : nazanine-modjtahedi
- ORCID : 0000-0002-1832-0710
- IdRef : 139178643
Guido Kroemer
- Fonction : Auteur
- PersonId : 758378
- ORCID : 0000-0002-9334-4405
- IdRef : 071283250
Résumé
Syncytia arising from the fusion of cells expressing the HIV-1-encoded Env gene with cells expressing the CD4/CXCR4 complex undergo apoptosis following the nuclear translocation of mammalian target of rapamycin (mTOR), mTOR-mediated phosphorylation of p53 on Ser15 (p53(S15)), p53-dependent upregulation of Bax and activation of the mitochondrial death pathway. p53(S15) phosphorylation is only detected in syncytia in which nuclear fusion (karyogamy) has occurred. Karyogamy is secondary to a transient upregulation of cyclin B and a mitotic prophase-like dismantling of the nuclear envelope. Inhibition of cyclin-dependent kinase-1 (Cdk1) prevents karyogamy, mTOR activation, p53(S15) phosphorylation and apoptosis. Neutralization of p53 fails to prevent karyogamy, yet suppresses apoptosis. Peripheral blood mononuclear cells from HIV-1-infected patients exhibit an increase in cyclin B and mTOR expression, correlating with p53(S15) phosphorylation and viral load. Cdk1 inhibition prevents the death of syncytia elicited by HIV-1 infection of primary CD4 lymphoblasts. Thus, HIV-1 elicits a pro-apoptotic signal transduction pathway relying on the sequential action of cyclin B-Cdk1, mTOR and p53.