title: p53 signalling controls cell cycle arrest and caspase-independent apoptosis in macrophages infected with pathogenic Leptospira species.
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.
authors.affiliation: Division of Basic Medical Microbiology, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China; Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
authors.forename: Weilin
authors.initials: W
authors.lastname: Hu
authors.forename: Yumei
authors.initials: Y
authors.lastname: Ge
authors.forename: David M
authors.initials: DM
authors.lastname: Ojcius
authors.forename: Dexter
authors.initials: D
authors.lastname: Sun
authors.forename: Haiyan
authors.initials: H
authors.lastname: Dong
authors.forename: X Frank
authors.initials: XF
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Yan
mesh_terms: D000818:Animals; D017209:Apoptosis; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D059447:Cell Cycle Checkpoints; D002478:Cells, Cultured; D004249:DNA Damage; D004706:Endodeoxyribonucleases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007921:Leptospira interrogans / Q000502:physiology*; D008264:Macrophages / Q000382:microbiology* / Q000502:physiology; D051379:Mice; D017382:Reactive Oxygen Species / Q000378:metabolism / Q000633:toxicity; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D051033:Apoptosis Inducing Factor; C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; C498301:TP53BP1 protein, human; D016159:Tumor Suppressor Protein p53; D000071857:Tumor Suppressor p53-Binding Protein 1; D004706:Endodeoxyribonucleases; C052391:endonuclease G