Macrophage apoptosis by anthrax lethal factor through p38 MAP kinase inhibition.
The bacterium Bacillus anthracis causes the death of macrophages, which may allow it to avoid detection by the innate immune system. We found that B. anthracis lethal factor (LF) selectively induces apoptosis of activated macrophages by cleaving the amino-terminal extension of mitogen-activated protein kinase (MAPK) kinases (MKKs) that activate p38 MAPKs. Because macrophages that are deficient in transcription factor nuclear factor kappaB (NF-kappaB) are also sensitive to activation-induced death and p38 is required for expression of certain NF-kappaB target genes, p38 is probably essential for synergistic induction of those NF-kappaB target genes that prevent apoptosis of activated macrophages. This dismantling of the p38 MAPK module represents a strategy used by B. anthracis to paralyze host innate immunity.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0636, USA.
Jin Mo
JM
Park
Florian R
FR
Greten
Zhi-Wei
ZW
Li
Michael
M
Karin
D000818:Animals; D000942:Antigens, Bacterial; D017209:Apoptosis; D001427:Bacterial Toxins / Q000633:toxicity*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000633:toxicity*; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D051550:I-kappa B Kinase; D007093:Imidazoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D020935:MAP Kinase Signaling System; D008262:Macrophage Activation; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009336:Necrosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D013682:Teichoic Acids / Q000494:pharmacology; D051996:Transcription Factor RelA; D048051:p38 Mitogen-Activated Protein Kinases
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011725:Pyridines; D013682:Teichoic Acids; D051996:Transcription Factor RelA; C030325:anthrax toxin; C009900:lipoteichoic acid; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482531:Map2k3 protein, mouse; C482567:Map2k6 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole