P53 Signalling Controls Cell Cycle Arrest And Caspase-Independent Apoptosis In Macrophages Infected With Pathogenic Leptospira Species

Weilin Hu, Yumei Ge, David M. Ojcius, Dexter Sun, Haiyan Dong, X. Frank Yang, Jie Yan

Research output: Contribution to journalArticle

46 Scopus citations


Summary: 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 p21Cip1/WAF1 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.

Original languageEnglish (US)
Pages (from-to)1624-1659
Number of pages36
JournalCellular Microbiology
Issue number10
StatePublished - Oct 1 2013


ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Virology

Cite this