Anthrax lethal factor cleaves MKK3 in macrophages and inhibits the LPS/IFNgamma-induced release of NO and TNFalpha.
The lethal toxin of Bacillus anthracis consists of two proteins, PA and LF, which together induce lethal effects in animals and cause macrophage lysis. LF is a zinc-endopeptidase which cleaves two mitogen-activated protein kinase kinases (MAPKKs), Mek1 and Mek2, within the cytosol. Here, we show that also MKK3, another dual-specificity kinase that phosphorylates and activates p38 MAP kinase, is cleaved by LF in macrophages. No direct correlation between LF-induced cell death and cleavage of these MAPKKs was found in macrophage cell lines and primary peritoneal cells exhibiting different sensitivity to LF. However, we present the first evidence that sublytic doses of LF cleave Meks and cause a substantial reduction in the production of NO and tumour necrosis factor-alpha induced by lipopolysaccharide/interferon gamma. We suggest that this effect of LF is relevant during the first stages of B. anthracis infection, when a reduction of the inflammatory response would permit growth and diffusion of the bacterium.
Pellizzari
R
R
Centro CNR Biomembrane and Dipartimento di Scienze Biomediche, Università di Padova, via Colombo 3, 35121, Padua, Italy.
Guidi-Rontani
C
C
Vitale
G
G
Mock
M
M
Montecucco
C
C
D000818:Animals; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism / Q000633:toxicity*; D002478:Cells, Cultured; D004347:Drug Interactions; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D048370:MAP Kinase Kinase 2; D048371:MAP Kinase Kinase 3; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C030325:anthrax toxin; D009569:Nitric Oxide; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D048370:MAP Kinase Kinase 2; D048371:MAP Kinase Kinase 3; C482531:Map2k3 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases