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 κB 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.
Protective Role of Raf-1 in Salmonella-Induced Macrophage Apoptosis
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.
Veronika Jesenberger, Katarzyna J. Procyk, Jochen Rüth, Martin Schreiber, Hans-Christian Theussl, Erwin F. Wagner, Manuela Baccarini; Protective Role of Raf-1 in Salmonella-Induced Macrophage Apoptosis. J Exp Med 5 February 2001; 193 (3): 353–364. doi: https://doi.org/10.1084/jem.193.3.353
Download citation file:
Sign in
Client Account
Sign in via your Institution
Sign in via your InstitutionSuggested Content
Email alerts
Advertisement