Biochem. J. (2007) 402
(405–417) (Printed in Great Britain)
Review article
Manipulation of host signalling pathways by anthrax toxins
Benjamin E. TURK1
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, U.S.A.
Infectious microbes face an unwelcoming environment in their mammalian hosts, which have evolved elaborate multicelluar systems for recognition and elimination of invading pathogens. A common strategy used by pathogenic bacteria to establish infection is to secrete protein factors that block intracellular signalling pathways essential for host defence. Some of these proteins also act as toxins, directly causing pathology associated with disease. Bacillus anthracis, the bacterium that causes anthrax, secretes two plasmid-encoded enzymes, LF (lethal factor) and EF (oedema factor), that are delivered into host cells by a third bacterial protein, PA (protective antigen). The two toxins act on a variety of cell types, disabling the immune system and inevitably killing the host. LF is an extraordinarily selective metalloproteinase that site-specifically cleaves MKKs (mitogen-activated protein kinase kinases). Cleavage of MKKs by LF prevents them from activating their downstream MAPK (mitogen-activated protein kinase) substrates by disrupting a critical docking interaction. Blockade of MAPK signalling functionally impairs cells of both the innate and adaptive immune systems and induces cell death in macrophages. EF is an adenylate cyclase that is activated by calmodulin through a non-canonical mechanism. EF causes sustained and potent activation of host cAMP-dependent signalling pathways, which disables phagocytes. Here I review recent progress in elucidating the mechanisms by which LF and EF influence host signalling and thereby contribute to disease.
Key words: adenylate cyclase, anthrax, lethal factor, oedema factor, metalloproteinase, mitogen-activated protein kinase pathway.
Abbreviations used: AC, adenylate cyclase; Apaf-1, apoptotic protease-activating factor 1; ARE, AU-rich element; ASC, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain; BAD, Bcl-2/Bcl-XL-antagonist, causing cell death; BIM, Bcl-2-interacting mediator of cell death; CaM, calmodulin; CARD, caspase activation and recruitment domain; CREB, cAMP-response element-binding protein; EdTx, oedema toxin; EF, oedema factor; eIF-2a, eukaryotic initiation factor-2a; ERK, extracellular-signal-regulated kinase; GR, glucocorticoid receptor; GSK, glycogen synthase kinase; hnRNP, heterogeneous nuclear ribonucleoprotein; IKK, IkB kinase; IL, interleukin; JNK, c-Jun N-terminal kinase; LeTx, lethal toxin; LF, lethal factor; LFIR, LF-interacting region; LPS, lipopolysaccharide; LRP6, low-density lipoprotein receptor-related protein 6; LRR, leucine-rich repeat; MAPK, mitogen-activated protein kinase; MAPKAP, MAPK-activated protein kinase; MKK, MAPK kinase; MKKK, MKK kinase; NF-kB, nuclear factor kB; PA, protective antigen; PAI-2, plasminogen-activator inhibitor 2; PAMP, pathogen-associated molecular pattern; PKA, cAMP-dependent protein kinase; PKB, protein kinase B; PKR, protein kinase R; RSK, p90 ribosomal S6 kinase; TLR, Toll-like receptor; TNFa, tumour necrosis factor a; TTSS, type III secretion system; UTR, untranslated region.
1email ben.turk@yale.edu
Received 18 December 2006/15 January 2007; accepted 16 January 2007
Published on the Internet 26 February 2007, doi:10.1042/BJ20061891
The Biochemical Society, London ©2007
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