p53 signalling controls cell cycle arrest and caspase-independent apoptosis in macrophages infected with pathogenic Leptospira species.
Cell Microbiol
; 15(10): 1642-59, 2013 Oct.
Article
em En
| MEDLINE
| ID: mdl-23521874
ABSTRACT
Pathogenic Leptospira species, the causative agents of leptospirosis, have been shown to induce macrophage apoptosis through caspase-independent, mitochondrion-related apoptosis inducing factor (AIF) and endonuclease G (EndoG), but the signalling pathway leading to AIF/EndoG-based macrophage apoptosis remains unknown. Here we show that infection of Leptospira interrogans caused a rapid increase in reactive oxygen species (ROS), DNA damage, and intranuclear foci of 53BP1 and phosphorylation of H2AX (two DNAdamage indicators) in wild-type p53-containing mouse macrophages and p53-deficient human macrophages. Most leptospire-infected cells stayed at the G1 phase, whereas depletion or inhibition of p53 caused a decrease of the G1 -phase cells and the early apoptotic ratios. Infection with spirochaetes stimulated a persistent activation of p53 and an early activation of Akt through phosphorylation. The intranuclear translocation of p53, increased expression of p53-dependent p21(Cip) (1/) (WAF) (1) and pro-apoptotic Bcl-2 family proteins (Bax, Noxa and Puma), release of AIF and EndoG from mitochondria, and membrane translocation of Fas occurred during leptospire-induced macrophage apoptosis. Thus, our study demonstrated that ROS production and DNA damage-dependent p53-Bax/Noxa/Puma-AIF/EndoG signalling mediates the leptospire-induced cell cycle arrest and caspase-independent apoptosis of macrophages.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
/
Proteína Supressora de Tumor p53
/
Apoptose
/
Interações Hospedeiro-Patógeno
/
Pontos de Checagem do Ciclo Celular
/
Leptospira interrogans
/
Macrófagos
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
China