Protective role of Raf-1 in Salmonella-induced macrophage apoptosis.
Invasive Salmonella induces macrophage apoptosis via the activation of caspase-1 by the bacterial protein SipB. Here we show that infection of macrophages with Salmonella causes the activation and degradation of Raf-1, an important intermediate in macrophage proliferation and activation. Raf-1 degradation is SipB- and caspase-1-dependent, and is prevented by proteasome inhibitors. To study the functional significance of Raf-1 in this process, the c-raf-1 gene was inactivated by Cre-loxP-mediated recombination in vivo. Macrophages lacking c-raf-1 are hypersensitive towards pathogen-induced apoptosis. Surprisingly, activation of the antiapoptotic mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and nuclear factor kappaB pathways is normal in Raf-1-deficient macrophages, and mitochondrial fragility is not increased. Instead, pathogen-mediated activation of caspase-1 is enhanced selectively, implying that Raf-1 antagonizes stimulus-induced caspase-1 activation and apoptosis.
Jesenberger
V
V
Department of Cell and Microbiology, Institute of Microbiology and Genetics, Vienna Biocenter, Austria.
Procyk
K J
KJ
Rüth
J
J
Schreiber
M
M
Theussl
H C
HC
Wagner
E F
EF
Baccarini
M
M
D000818:Animals; D017209:Apoptosis; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D007976:Leupeptins / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism / Q000502:physiology*; D012486:Salmonella typhimurium / Q000502:physiology*
D001426:Bacterial Proteins; D007976:Leupeptins; D008565:Membrane Proteins; D016328:NF-kappa B; D011480:Protease Inhibitors; C089486:carbobenzoxy-leucyl-leucyl-norvalinal; C094579:invasion protein B, Salmonella typhimurium; D019908:Proto-Oncogene Proteins c-raf; D020928:Mitogen-Activated Protein Kinases; D020170:Caspase 1; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde