Anthrax Edema Factor Toxicity is Strongly Mediated by the N-end Rule

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Sep 10

PMID 24015319

Citations 10

Authors

Clinton E Leysath

Damilola D Phillips

Devorah Crown

Rasem J Fattah

Mahtab Moayeri

Stephen H Leppla

Affiliations

Soon will be listed here.

Abstract

Anthrax edema factor (EF) is a calmodulin-dependent adenylate cyclase that converts adenosine triphosphate (ATP) into 3'-5'-cyclic adenosine monophosphate (cAMP), contributing to the establishment of Bacillus anthracis infections and the resulting pathophysiology. We show that EF adenylate cyclase toxin activity is strongly mediated by the N-end rule, and thus is dependent on the identity of the N-terminal amino acid. EF variants having different N-terminal residues varied by more than 100-fold in potency in cultured cells and mice. EF variants having unfavorable, destabilizing N-terminal residues showed much greater activity in cells when the E1 ubiquitin ligase was inactivated or when proteasome inhibitors were present. Taken together, these results show that EF is uniquely affected by ubiquitination and/or proteasomal degradation.

Citing Articles

Early Circulating Edema Factor in Inhalational Anthrax Infection: Does It Matter?.

Tessier E, Cheutin L, Garnier A, Vigne C, Tournier J, Rougeaux C Microorganisms. 2024; 12(2).

PMID: 38399712 PMC: 10891819. DOI: 10.3390/microorganisms12020308.

Protein Arginylation Is Regulated during SARS-CoV-2 Infection.

Macedo-da-Silva J, Rosa-Fernandes L, de Morais Gomes V, Feijoli Santiago V, Santos D, Molnar C Viruses. 2023; 15(2).

PMID: 36851505 PMC: 9964439. DOI: 10.3390/v15020290.

Anthrax toxins regulate pain signaling and can deliver molecular cargoes into ANTXR2 DRG sensory neurons.

Yang N, Isensee J, Neel D, Quadros A, Zhang H, Lauzadis J Nat Neurosci. 2021; 25(2):168-179.

PMID: 34931070 PMC: 9388775. DOI: 10.1038/s41593-021-00973-8.

Nociceptive Sensory Neurons Mediate Inflammation Induced by Edema Toxin.

Yang N, Neel D, Deng L, Heyang M, Kennedy-Curran A, Tong V Front Immunol. 2021; 12:642373.

PMID: 34413846 PMC: 8369925. DOI: 10.3389/fimmu.2021.642373.

Bismaleimide cross-linked anthrax toxin forms functional octamers with high specificity in tumor targeting.

Fischer E, Campbell 4th W, Liu S, Ghirlando R, Fattah R, Bugge T Protein Sci. 2019; 28(6):1059-1070.

PMID: 30942916 PMC: 6511737. DOI: 10.1002/pro.3613.

References

Leppla S . Anthrax toxin edema factor: a bacterial adenylate cyclase that increases cyclic AMP concentrations of eukaryotic cells. Proc Natl Acad Sci U S A. 1982; 79(10):3162-6. PMC: 346374. DOI: 10.1073/pnas.79.10.3162. View

KULKA R, Raboy B, Schuster R, Parag H, Diamond G, Ciechanover A . A Chinese hamster cell cycle mutant arrested at G2 phase has a temperature-sensitive ubiquitin-activating enzyme, E1. J Biol Chem. 1988; 263(30):15726-31. View

Gupta P, Moayeri M, Crown D, Fattah R, Leppla S . Role of N-terminal amino acids in the potency of anthrax lethal factor. PLoS One. 2008; 3(9):e3130. PMC: 2518864. DOI: 10.1371/journal.pone.0003130. View

Leysath C, Chen K, Moayeri M, Crown D, Fattah R, Chen Z . Mouse monoclonal antibodies to anthrax edema factor protect against infection. Infect Immun. 2011; 79(11):4609-16. PMC: 3257937. DOI: 10.1128/IAI.05314-11. View

Wickliffe K, Leppla S, Moayeri M . Killing of macrophages by anthrax lethal toxin: involvement of the N-end rule pathway. Cell Microbiol. 2008; 10(6):1352-62. PMC: 2500182. DOI: 10.1111/j.1462-5822.2008.01131.x. View

Ho S, Hunt H, Horton R, Pullen J, Pease L . Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene. 1989; 77(1):51-9. DOI: 10.1016/0378-1119(89)90358-2. View

Newman Z, Printz M, Liu S, Crown D, Breen L, Miller-Randolph S . Susceptibility to anthrax lethal toxin-induced rat death is controlled by a single chromosome 10 locus that includes rNlrp1. PLoS Pathog. 2010; 6(5):e1000906. PMC: 2873920. DOI: 10.1371/journal.ppat.1000906. View

Varshavsky A . The N-end rule at atomic resolution. Nat Struct Mol Biol. 2008; 15(12):1238-40. DOI: 10.1038/nsmb1208-1238. View

Firoved A, Miller G, Moayeri M, Kakkar R, Shen Y, Wiggins J . Bacillus anthracis edema toxin causes extensive tissue lesions and rapid lethality in mice. Am J Pathol. 2005; 167(5):1309-20. PMC: 1603774. DOI: 10.1016/S0002-9440(10)61218-7. View

10.

Hellmich K, Levinsohn J, Fattah R, Newman Z, Maier N, Sastalla I . Anthrax lethal factor cleaves mouse nlrp1b in both toxin-sensitive and toxin-resistant macrophages. PLoS One. 2012; 7(11):e49741. PMC: 3495862. DOI: 10.1371/journal.pone.0049741. View

11.

Newman Z, Crown D, Leppla S, Moayeri M . Anthrax lethal toxin activates the inflammasome in sensitive rat macrophages. Biochem Biophys Res Commun. 2010; 398(4):785-9. PMC: 2925535. DOI: 10.1016/j.bbrc.2010.07.039. View

12.

Duesbery N, Webb C, Leppla S, Gordon V, Klimpel K, Copeland T . Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science. 1998; 280(5364):734-7. DOI: 10.1126/science.280.5364.734. View

13.

Park S, Leppla S . Optimized production and purification of Bacillus anthracis lethal factor. Protein Expr Purif. 2000; 18(3):293-302. DOI: 10.1006/prep.2000.1208. View

14.

Dumetz F, Jouvion G, Khun H, Glomski I, Corre J, Rougeaux C . Noninvasive imaging technologies reveal edema toxin as a key virulence factor in anthrax. Am J Pathol. 2011; 178(6):2523-35. PMC: 3124019. DOI: 10.1016/j.ajpath.2011.02.027. View

15.

Varshavsky A . The N-end rule pathway of protein degradation. Genes Cells. 1997; 2(1):13-28. DOI: 10.1046/j.1365-2443.1997.1020301.x. View

16.

Nilsson I, von Heijne G . A signal peptide with a proline next to the cleavage site inhibits leader peptidase when present in a sec-independent protein. FEBS Lett. 1992; 299(3):243-6. DOI: 10.1016/0014-5793(92)80124-y. View

17.

Shen Y, Zhukovskaya N, Guo Q, Florian J, Tang W . Calcium-independent calmodulin binding and two-metal-ion catalytic mechanism of anthrax edema factor. EMBO J. 2005; 24(5):929-41. PMC: 554124. DOI: 10.1038/sj.emboj.7600574. View

18.

Barkocy-Gallagher G, Bassford Jr P . Synthesis of precursor maltose-binding protein with proline in the +1 position of the cleavage site interferes with the activity of Escherichia coli signal peptidase I in vivo. J Biol Chem. 1992; 267(2):1231-8. View

19.

Pomerantsev A, Pomerantseva O, Moayeri M, Fattah R, Tallant C, Leppla S . A Bacillus anthracis strain deleted for six proteases serves as an effective host for production of recombinant proteins. Protein Expr Purif. 2011; 80(1):80-90. PMC: 3183367. DOI: 10.1016/j.pep.2011.05.016. View

20.

Moayeri M, Leppla S . Cellular and systemic effects of anthrax lethal toxin and edema toxin. Mol Aspects Med. 2009; 30(6):439-55. PMC: 2784088. DOI: 10.1016/j.mam.2009.07.003. View