title: Anthrax lethal toxin inhibits translation of hypoxia-inducible factor 1α and causes decreased tolerance to hypoxic stress.
abstract: Hypoxia is considered to be a contributor to the pathology associated with administration of anthrax lethal toxin (LT). However, we report here that serum lactate levels in LT-treated mice are reduced, a finding inconsistent with the anaerobic metabolism expected to occur during hypoxia. Reduced lactate levels are also observed in the culture supernatants of LT-treated cells. LT inhibits the accumulation of hypoxia-inducible factor (HIF)-1α, a subunit of HIF-1, the master regulator directing cellular responses to hypoxia. The toxin has no effect on the transcription or protein turnover of HIF-1α, but instead it acts to inhibit HIF-1α translation. LT treatment diminishes phosphorylation of eIF4B, eIF4E, and rpS6, critical components of the intracellular machinery required for HIF-1α translation. Moreover, blockade of MKK1/2-ERK1/2, but not p38 or JNK signaling, lowers HIF-1α protein levels in both normoxic and hypoxic conditions, consistent with a role for MKK1 and MKK2 as the major targets of LT responsible for the inhibition of HIF-1α translation. The physiological importance of the LT-induced translation blockade is demonstrated by the finding that LT treatment decreases the survival of hepatocyte cell lines grown in hypoxic conditions, an effect that is overcome by preinduction of HIF-1α. Taken together, these data support a role for LT in dysregulating HIF-1α and thereby disrupting homeostatic responses to hypoxia, an environmental characteristic of certain tissues at baseline and/or during disseminated infection with Bacillus anthracis.
authors.affiliation: From the Division of Monoclonal Antibodies, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, United States Food and Drug Administration, Bethesda, Maryland 20892.
authors.forename: Weiming
authors.initials: W
authors.lastname: Ouyang
authors.forename: Chikako
authors.initials: C
authors.lastname: Torigoe
authors.forename: Hui
authors.initials: H
authors.lastname: Fang
authors.forename: Tao
authors.initials: T
authors.lastname: Xie
authors.forename: David M
authors.initials: DM
authors.lastname: Frucht
mesh_terms: D000818:Animals; D000881:Anthrax / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000942:Antigens, Bacterial / Q000378:metabolism*; D001408:Bacillus anthracis / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D010766:Phosphorylation / Q000235:genetics; D014176:Protein Biosynthesis; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; C497442:HIF1A protein, human; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D038601:Ribosomal Protein S6; C030325:anthrax toxin; C031799:eIF-4B; C448579:ribosomal protein S6, mouse; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Bacillus; Bacterial Pathogenesis; Hypoxia; Hypoxia-inducible Factor; Infectious Diseases; MAP kinases (MAPKs); Protein Stability; Toxins; Translation; mTOR