The Journal of Experimental Medicine
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Published online 5 February 2001.
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© The Rockefeller University Press, 0022-1007/2001/2/353/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 3, February 5, 2001 353-364

Original Article

Protective Role of Raf-1 in Salmonella-Induced Macrophage Apoptosis

Veronika Jesenbergera, Katarzyna J. Procyka, Jochen Rütha, Martin Schreibera, Hans-Christian Theusslb, Erwin F. Wagnerb, and Manuela Baccarinia

a Department of Cell and Microbiology, Institute of Microbiology and Genetics,
b Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria
Dept. of Cell and Microbiology, Institute of Microbiology and Genetics, Vienna Biocenter, Dr-Bohrgasse 9, 1030 Vienna, Austria.43-1-4277-954643-1-4277-54607

manuela{at}gem.univie.ac.at

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 {kappa}B 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.

Key Words: serine/threonine kinase • cell death • bacteria • proteases • monocytes/macrophages

Abbreviations used in this paper: ERK, extracellular signal–regulated kinase; ES, embryonic stem; floxed, flanked by loxP sites; HMF, heavy membrane fraction; IAP, inhibitor of apoptosis; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK or ERK kinase; moi, multiplicity of infection; NF, nuclear factor; poly I:C, poly inosinic:cytidyllic acid; Q/W, quenching/washing solution; RT, room temperature; SPI, Salmonella pathogenicity island; wt, wild-type.

K.J. Procyk's present address is Protein Phosphorylation Lab, Imperial Cancer Research Fund, London WC2A 3PX, UK. M. Schreiber's present address is Department of Obstetrics and Gynecology, University of Vienna, A-1090 Vienna, Austria.

© 2001 The Rockefeller University Press


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