title: Auranofin protects against anthrax lethal toxin-induced activation of the Nlrp1b inflammasome.
abstract: Anthrax lethal toxin (LT) is the major virulence factor for Bacillus anthracis. The lethal factor (LF) component of this bipartite toxin is a protease which, when transported into the cellular cytoplasm, cleaves mitogen-activated protein kinase kinase (MEK) family proteins and induces rapid toxicity in mouse macrophages through activation of the Nlrp1b inflammasome. A high-throughput screen was performed to identify synergistic LT-inhibitory drug combinations from within a library of approved drugs and molecular probes. From this screen we discovered that auranofin, an organogold compound with anti-inflammatory activity, strongly inhibited LT-mediated toxicity in mouse macrophages. Auranofin did not inhibit toxin transport into cells or MEK cleavage but inhibited both LT-mediated caspase-1 activation and caspase-1 catalytic activity. Thus, auranofin inhibited LT-mediated toxicity by preventing activation of the Nlrp1b inflammasome and the downstream actions that occur in response to the toxin. Idebenone, an analog of coenzyme Q, synergized with auranofin to increase its protective effect. We found that idebenone functions as an inhibitor of voltage-gated potassium channels and thus likely mediates synergy through inhibition of the potassium fluxes which have been shown to be required for Nlrp1b inflammasome activation.
authors.affiliation: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Newman
authors.forename: Nicole
authors.initials: N
authors.lastname: Sirianni
authors.forename: Christina
authors.initials: C
authors.lastname: Mawhinney
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Lee
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Johansen
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000633:toxicity*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001310:Auranofin / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000633:toxicity*; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; D053583:Interleukin-1beta; C509168:Nalp1b protein, mouse; C030325:anthrax toxin; D001310:Auranofin; D020929:Mitogen-Activated Protein Kinase Kinases; D020170:Caspase 1