Anthrax answers

Abstract

Seldom does toxin research hit the headlines of the newspapers, but recently Duesbery et al.[1]achieved this accolade because of the relevance of their research to warfare. This group have unravelled the target of the enzymatic action of one component of lethal toxin [lethal factor (LF)] of Bacillus anthracis, the bacteria responsible for anthrax. Previous research had provided strong evidence that LF acts as an intracellular metalloprotease. Now, Duesbery et al.[1], followed by Vitale et al.[2], have identified the mitogen-activated protein kinase (MAPK) kinase as the target of its enzymatic action. LF cleaves few residues from the amino terminus of both isoforms of MAPK kinase. This appears to be a critical deletion, as the removal of this region blocks the interaction with the substrate and, consequently, the MAPK kinase signal transduction cascade involved in cell proliferation, oocyte maturation and embryo development. As Duesbury et al.[1]readily acknowledge, the pathway leading to their important discovery was purely serendipitous. In their search for compounds acting on the MAPK pathway, they found that the effects of LF on a panel of tumour cell lines mimic the action of the known MAPK kinase inhibitor PD09859, one of more than 60 000 compounds screened by the National Cancer Institute for anti-tumour activity. In a remarkable example of convergent research, the same conclusion has been independently reached by Vitale et al.[2]. Using a yeast two-hybrid strategy with an active site LF mutant devoid of proteolytic activity as bait, they found MAPK kinases 1 and 2 as preys in their assay. The fact that two independent screenings have highlighted MAPK kinases as targets of LF suggests a key role for these proteins in LF-induced toxicity. However, both groups have failed to correlate the cleavage of MAPK kinases with the LF-induced death of macrophages, let alone the death of animals. What emerges is a very exciting discovery that provides cell biologists with a new tool to knock out the ubiquitous MAPK kinases and to test their role in cell activation pathways. In addition, these studies open the way for the design of LF inhibitors to be tested as potential anti-anthrax drugs.