p53 signalling controls cell cycle arrest and caspase-independent apoptosis in macrophages infected with pathogenic Leptospira species
Authors: Haiyan Dong
Dexter Sun
Yumei Ge
Jie Yan
Weilin Hu
X Frank Yang
David M Ojcius
Journal: Cellular Microbiology (2013)
Discipline: MICROBIOLOGY
Keywords: Leptospira species; macrophage apoptosis; p53; ROS; DNA damage
Affiliations: 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., Department of Medical Microbiology and Parasitology; Zhejiang University School of Medicine; Hangzhou; Zhejiang; 310058; China, Health Sciences Research Institute and Molecular Cell Biology; University of California; Merced; CA; 95343; USA, Department of Neurology and Neuroscience; New York Presbyterian Hospital and Hospital for Special Surgery, Cornell University Weill Medical College; New York; NY; 10021; USA, Department of Medical Microbiology and Immunology; Wenzhou Medical College; Wenzhou; Zhejiang; 325000; China, Department of Microbiology and Immunology; Indiana University School of Medicine; Indianapolis; IN; 46202; USA

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. 

Retracted: No

PubPeer comments:
 Figure 6A: * Red boxes: In the THP-1 cells panel, the p53-pho (S15) and p53-pho (S46) panels appear to show an overlap. Image made darker to bring out details. ![file] Here is a close up view of those right-hand panels. ![file] , 
 In Figure 5A, the  p53 panel representing THP-1 cells also looks familiar. It appears to be a different antibody incubation than the p53-Ser15 or p53-Ser46 panels in Figure 6A. Maybe the authors can clarify? ![file] , 
 Corrigendum, October 2020: https: onlinelibrary.wiley.com doi 10.1111 cmi.13265  The authors of the article by Hu et al. (2013) would like to report a mistake in Figure 6A. In the published version of Figure 6A, the panels of the u201cp53-pho(S15)u201d and u201cp53-pho(S46)u201d groups in THP-1 cells were inadvertently shown with incorrect images. The amended version of Figure 6A can be found below. The error does not affect the results or conclusions of the article. The authors would like to apologize for the inconvenience caused by this error. ,