Yu H, Schwarzer K, FÃ¶rster M, Kniemeyer O, Forsbach-Birk V, Straube E, RÃ¶del J
Role of high-mobility group box 1 protein and poly(ADP-ribose) polymerase 1 degradation in Chlamydia trachomatis-induced cytopathicity.
Infect Immun. 2010 Jul;78(7):3288-97
Authors: Yu H, Schwarzer K, FÃ¶rster M, Kniemeyer O, Forsbach-Birk V, Straube E, RÃ¶del J
As intracellular bacteria, chlamydiae block the apoptotic pathways of their host cells. However, the infection of epithelial cells causes the loss of cell membrane integrity and can result in nonapoptotic death. Normally, cells undergoing necrosis release high-mobility group box 1 protein (HMGB1) that acts as an important proinflammatory mediator. Here, we show that in Chlamydia trachomatis-infected HeLa cells HMGB1 is not translocated from the nucleus to the cytosol and not released from injured cells in increased amounts. At 48 h after infection, degradation of HMGB1 was observed. In infected cells, poly(ADP-ribose) polymerase 1 (PARP-1), a DNA repair enzyme that also regulates HMGB1 translocation, was found to be cleaved into fragments that correspond to a necrosis like pattern of PARP-1 degradation. Cell-free cleavage assays and immunoprecipitation using purified proteolytic fractions from infected cells demonstrated that the chlamydial-protease-like activity factor (CPAF) is responsible for the cleavage of both HMGB1 and PARP-1. Proteolytic cleavage of PARP-1 was accompanied by a significant decrease in the enzymatic activity in a time-dependent manner. The loss of PARP-1 function obviously affects the viability of Chlamydia-infected cells because silencing of PARP-1 in uninfected HeLa cells with specific small interfering RNA results in increased cell membrane permeability. Our findings suggest that the Chlamydia-specific protease CPAF interferes with necrotic cell death pathways. By the degradation of HMGB1 and PARP-1, the pathogen may have evolved a strategy to reduce the inflammatory response to membrane-damaged cells in vivo.
PMID: 20421386 [PubMed - indexed for MEDLINE]