Human Alpha-defensins Neutralize Toxins of the Mono-ADP-ribosyltransferase Family

Overview

Journal Biochem J

Specialty Biochemistry

Date 2006 Jul 5

PMID 16817779

Citations 21

Authors

Chun Kim

Zoya Slavinskaya

A Rod Merrill

Stefan H E Kaufmann

Affiliations

Soon will be listed here.

Abstract

Various bacterial pathogens secrete toxins, which are not only responsible for fatal pathogenesis of disease, but also facilitate evasion of host defences. One of the best-known bacterial toxin groups is the mono-ADP-ribosyltransferase family. In the present study, we demonstrate that human neutrophil alpha-defensins are potent inhibitors of the bacterial enzymes, particularly against DT (diphtheria toxin) and ETA (Pseudomonas exotoxin A). HNP1 (human neutrophil protein 1) inhibited DT- or ETA-mediated ADP-ribosylation of eEF2 (eukaryotic elongation factor 2) and protected HeLa cells against DT- or ETA-induced cell death. Kinetic analysis revealed that inhibition of DT and ETA by HNP1 was competitive with respect to eEF2 and uncompetitive against NAD+ substrates. Our results reveal that toxin neutralization represents a novel biological function of HNPs in host defence.

Citing Articles

Promotion of Colitis in B Cell-Deficient C57BL/6 Mice Infected with Enterotoxigenic .

Jo M, Hwang S, Lee C, Hong J, Kang D, Yoo S Int J Mol Sci. 2024; 25(1).

PMID: 38203534 PMC: 10778593. DOI: 10.3390/ijms25010364.

Inhibition of Pertussis Toxin by Human α-Defensins-1 and -5: Differential Mechanisms of Action.

Kling C, Sommer A, Almeida-Hernandez Y, Rodriguez A, Perez-Erviti J, Bhadane R Int J Mol Sci. 2023; 24(13).

PMID: 37445740 PMC: 10341622. DOI: 10.3390/ijms241310557.

Host Cationic Antimicrobial Molecules Inhibit S. aureus Exotoxin Production.

Schlievert P, Kilgore S, Beck L, Yoshida T, Klingelhutz A, Leung D mSphere. 2023; 8(1):e0057622.

PMID: 36598227 PMC: 9942567. DOI: 10.1128/msphere.00576-22.

Synthesis of an Anti-CD7 Recombinant Immunotoxin Based on PE24 in CHO and Cell-Free Systems.

Krebs S, Stech M, Jorde F, Rakotoarinoro N, Ramm F, Marinoff S Int J Mol Sci. 2022; 23(22).

PMID: 36430170 PMC: 9697001. DOI: 10.3390/ijms232213697.

Human α-Defensin-6 Neutralizes Toxins TcdA and TcdB by Direct Binding.

Barthold L, Heber S, Schmidt C, Gradl M, Weidinger G, Barth H Int J Mol Sci. 2022; 23(9).

PMID: 35562899 PMC: 9101188. DOI: 10.3390/ijms23094509.

References

Armstrong S, Merrill A . Application of a fluorometric assay for characterization of the catalytic competency of a domain III fragment of Pseudomonas aeruginosa exotoxin A. Anal Biochem. 2001; 292(1):26-33. DOI: 10.1006/abio.2001.5052. View

Domenighini M, Rappuoli R . Three conserved consensus sequences identify the NAD-binding site of ADP-ribosylating enzymes, expressed by eukaryotes, bacteria and T-even bacteriophages. Mol Microbiol. 1996; 21(4):667-74. DOI: 10.1046/j.1365-2958.1996.321396.x. View

Han S, Tainer J . The ARTT motif and a unified structural understanding of substrate recognition in ADP-ribosylating bacterial toxins and eukaryotic ADP-ribosyltransferases. Int J Med Microbiol. 2002; 291(6-7):523-9. DOI: 10.1078/1438-4221-00162. View

Paone G, Wada A, Stevens L, Matin A, Hirayama T, Levine R . ADP ribosylation of human neutrophil peptide-1 regulates its biological properties. Proc Natl Acad Sci U S A. 2002; 99(12):8231-5. PMC: 123050. DOI: 10.1073/pnas.122238899. View

Yang D, Biragyn A, Kwak L, Oppenheim J . Mammalian defensins in immunity: more than just microbicidal. Trends Immunol. 2002; 23(6):291-6. DOI: 10.1016/s1471-4906(02)02246-9. View

Nassar T, Akkawi S, Bar-Shavit R, Haj-Yehia A, Bdeir K, Al-Mehdi A . Human alpha-defensin regulates smooth muscle cell contraction: a role for low-density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. Blood. 2002; 100(12):4026-32. DOI: 10.1182/blood-2002-04-1080. View

Corda D, Di Girolamo M . Mono-ADP-ribosylation: a tool for modulating immune response and cell signaling. Sci STKE. 2002; 2002(163):pe53. DOI: 10.1126/stke.2002.163.pe53. View

Armstrong S, Li J, Zhang J, Merrill A . Characterization of competitive inhibitors for the transferase activity of Pseudomonas aeruginosa exotoxin A. J Enzyme Inhib Med Chem. 2003; 17(4):235-46. DOI: 10.1080/1475636021000010914. View

Spahn C, Gomez-Lorenzo M, Grassucci R, Jorgensen R, Andersen G, Beckmann R . Domain movements of elongation factor eEF2 and the eukaryotic 80S ribosome facilitate tRNA translocation. EMBO J. 2004; 23(5):1008-19. PMC: 380967. DOI: 10.1038/sj.emboj.7600102. View

10.

Yates S, Merrill A . Elucidation of eukaryotic elongation factor-2 contact sites within the catalytic domain of Pseudomonas aeruginosa exotoxin A. Biochem J. 2004; 379(Pt 3):563-72. PMC: 1224111. DOI: 10.1042/BJ20031731. View

11.

Andersen C, Anand M, Boesen T, Van L, Kinzy T, Andersen G . Purification and crystallization of the yeast translation elongation factor eEF3. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 7):1304-7. DOI: 10.1107/S0907444904010716. View

12.

Ganz T . Defensins: antimicrobial peptides of vertebrates. C R Biol. 2004; 327(6):539-49. DOI: 10.1016/j.crvi.2003.12.007. View

13.

Okazaki I, Moss J . Mono-ADP-ribosylation: a reversible posttranslational modification of proteins. Adv Pharmacol. 1996; 35:247-80. DOI: 10.1016/s1054-3589(08)60277-x. View

14.

Braren R, Glowacki G, Nissen M, Haag F, Koch-Nolte F . Molecular characterization and expression of the gene for mouse NAD+:arginine ecto-mono(ADP-ribosyl)transferase, Art1. Biochem J. 1998; 336 ( Pt 3):561-8. PMC: 1219905. DOI: 10.1042/bj3360561. View

15.

Kim C, Gajendran N, Mittrucker H, Weiwad M, Song Y, Hurwitz R . Human alpha-defensins neutralize anthrax lethal toxin and protect against its fatal consequences. Proc Natl Acad Sci U S A. 2005; 102(13):4830-5. PMC: 555714. DOI: 10.1073/pnas.0500508102. View

16.

Yates S, Merrill A . Characterization of oxidized nicotinamide adenine dinucleotide (NAD(+)) analogues using a high-pressure-liquid-chromatography-based NAD(+)-glycohydrolase assay and comparison with fluorescence-based measurements. Anal Biochem. 2005; 340(1):41-51. DOI: 10.1016/j.ab.2005.01.051. View

17.

Jorgensen R, Merrill A, Yates S, Marquez V, Schwan A, Boesen T . Exotoxin A-eEF2 complex structure indicates ADP ribosylation by ribosome mimicry. Nature. 2005; 436(7053):979-84. DOI: 10.1038/nature03871. View

18.

Yates S, Jorgensen R, Andersen G, Merrill A . Stealth and mimicry by deadly bacterial toxins. Trends Biochem Sci. 2006; 31(2):123-33. DOI: 10.1016/j.tibs.2005.12.007. View

19.

Collier R, Kandel J . Structure and activity of diphtheria toxin. I. Thiol-dependent dissociation of a fraction of toxin into enzymically active and inactive fragments. J Biol Chem. 1971; 246(5):1496-503. View

20.

Drazin R, Kandel J, Collier R . Structure and activity of diphtheria toxin. II. Attack by trypsin at a specific site within the intact toxin molecule. J Biol Chem. 1971; 246(5):1504-10. View