Protective role of Raf-1 in Salmonella-induced macrophage apoptosis

V Jesenberger; K J Procyk; J Rüth; M Schreiber; H C Theussl; E F Wagner; M Baccarini

doi:10.1084/jem.193.3.353

Protective role of Raf-1 in Salmonella-induced macrophage apoptosis

J Exp Med. 2001 Feb 5;193(3):353-64. doi: 10.1084/jem.193.3.353.

Authors

V Jesenberger¹, K J Procyk, J Rüth, M Schreiber, H C Theussl, E F Wagner, M Baccarini

Affiliation

¹ Department of Cell and Microbiology, Institute of Microbiology and Genetics, Vienna Biocenter, Austria.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis*
Bacterial Proteins / genetics
Bacterial Proteins / metabolism
Bone Marrow Cells / cytology
Bone Marrow Cells / drug effects
Bone Marrow Cells / enzymology
Caspase 1 / metabolism
Cells, Cultured
Enzyme Activation
Leupeptins / pharmacology
Macrophages / cytology*
Macrophages / drug effects
Macrophages / enzymology
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Mitochondria / metabolism
Mitogen-Activated Protein Kinases / metabolism
NF-kappa B / metabolism
Protease Inhibitors / pharmacology
Proto-Oncogene Proteins c-raf / metabolism
Proto-Oncogene Proteins c-raf / physiology*
Salmonella typhimurium / physiology*

Substances

Bacterial Proteins
Leupeptins
Membrane Proteins
NF-kappa B
Protease Inhibitors
carbobenzoxy-leucyl-leucyl-norvalinal
invasion protein B, Salmonella typhimurium
Proto-Oncogene Proteins c-raf
Mitogen-Activated Protein Kinases
Caspase 1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde