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Angiogenins: a new class of microbicidal proteins involved in innate immunity

Nature Immunologyvolume 4pages269273 (2003) | Download Citation

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Abstract

Although angiogenins have been implicated in tumor-associated angiogenesis, their normal physiologic function remains unclear. We show that a previously uncharacterized angiogenin, Ang4, is produced by mouse Paneth cells, is secreted into the gut lumen and has bactericidal activity against intestinal microbes. Ang4 expression is induced by Bacteroides thetaiotaomicron, a predominant member of the gut microflora, revealing a mechanism whereby intestinal commensal bacteria influence gut microbial ecology and shape innate immunity. Furthermore, mouse Ang1 and human angiogenin, circulating proteins induced during inflammation, exhibit microbicidal activity against systemic bacterial and fungal pathogens, suggesting that they contribute to systemic responses to infection. These results establish angiogenins as a family of endogenous antimicrobial proteins.

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References

  1. 1

    Fett, J.W. et al. Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells. Biochemistry 24, 5480–5486 (1985).

  2. 2

    Kao, R.Y.T. et al. A small-molecule inhibitor of the ribonucleolytic activity of human angiogenin that possesses antitumor activity. Proc. Natl. Acad. Sci. USA 99, 10066–10071 (2002).

  3. 3

    Rybak, S.M., Fett, J.W., Yao, Q.Z. & Vallee, B.L. Angiogenin mRNA in human tumor and normal cells. Biochem. Biophys. Res. Commun. 146, 1240 (1987).

  4. 4

    Weiner, H.L., Weiner, L.H. & Swain, J.L. Tissue distribution and developmental expression of the messenger RNA encoding angiogenin. Science 237, 280–282 (1987).

  5. 5

    Olson, K.A., Verselis, S.J. & Fett, J.W. Angiogenin is regulated in vivo as an acute phase protein. Biochem. Biophys. Res. Commun. 242, 480–483 (1998).

  6. 6

    Zhang, J. & Rosenberg, H.F. Diversifying selection of the tumor-growth promoter angiogenin in primate evolution. Mol. Biol. Evol. 19, 438–445 (2002).

  7. 7

    Strydom, D.J. The angiogenins. Cell. Mol. Life Sci. 54, 811–824 (1998).

  8. 8

    Nobile, V., Vallee, B.L. & Shapiro, R. Characterization of mouse angiogenin-related protein: implications for functional studies on angiogenin. Proc. Natl. Acad. Sci. USA 93, 4331–4335 (1996).

  9. 9

    Fu, X., Roberts, W.G., Nobile, V., Shapiro, R. & Kamps, M.P. mAngiogenin-3, a target gene of oncoprotein E2a-Pbx1, encodes a new angiogenic member of the angiogenin family. Growth Factors 17, 125–137 (1999).

  10. 10

    Bry, L., Falk, P.G., Midtvedt, T. & Gordon, J.I. A model of host-microbial interactions in an open mammalian ecosystem. Science 273, 1380–1383 (1996).

  11. 11

    Hooper, L.V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001).

  12. 12

    Emmert-Buck, M.R. et al. Laser capture microdissection. Science 274, 998–1001 (1996).

  13. 13

    Garabedian, E.R., Roberts, L.J., McNevin, M.S. & Gordon, J.I. Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J. Biol. Chem. 272, 23729–23740 (1997).

  14. 14

    Ayabe, T. et al. Secretion of microbicidal α-defensins by intestinal Paneth cells in response to bacteria. Nat. Immunol. 1, 113–118 (2000).

  15. 15

    Holloway, D.E., Hares, M.C., Shapiro, R., Subramanian, V. & Acharya, K.R. High-level expression of three members of the murine angiogenin family in Escherichia coli and purification of the recombinant proteins. Protein Expr. Purif. 22, 307–317 (2001).

  16. 16

    Rosenberg, H.F. & Domachowske, J.B. Eosinophils, eosinophil ribonucleases, and their role in host defense against respiratory virus pathogens. J. Leukoc. Biol. 70, 691–698 (2001).

  17. 17

    Rosenberg, H.F. Recombinant human eosinophil cationic protein. Ribonuclease activity is not essential for cytotoxicity. J. Biol. Chem. 270, 7876–7881 (1995).

  18. 18

    Glaser, P. et al. Comparative genomics of Listeria species. Science 294, 849–852 (2001).

  19. 19

    Ghosh, D. et al. Paneth cell trypsin is the processing enzyme for human defensin-5. Nat. Immunol. 3, 583–590 (2002).

  20. 20

    Goldman, M.J. et al. Human β-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 88, 553–560 (1997).

  21. 21

    Lehrer, R.I., Lichtenstein, A.K. & Ganz, T. Defensins: antimicrobial and cytotoxic peptides of mammalian cells. Annu. Rev. Immunol. 11, 105–128 (1993).

  22. 22

    Panyutich, A.V., Hiemstra, P.S., van Wetering, S. & Ganz, T. Human neutrophil defensin and serpins form complexes and inactivate each other. Am. J. Respir. Cell. Mol. Biol. 12, 351–357 (1995).

  23. 23

    Panyutich, A.V., Szold, O., Poon, P.H., Tseng, Y. & Ganz, T. Identification of defensin binding to C1 complement. FEBS Lett. 356, 169–173 (1994).

  24. 24

    Saxena, S.K., Rybak, S.M., Davey, R.T. Jr., Youle, R.J. & Ackerman, E.J. Angiogenin is a cytotoxic, tRNA-specific ribonuclease in the RNase A superfamily. J. Biol. Chem. 267, 21982–21986 (1992).

  25. 25

    Savage, D.C. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 31, 107–133 (1977).

  26. 26

    Putsep, K. et al. Germ-free and colonized mice generate the same products from enteric prodefensins. J. Biol. Chem. 275, 40478–40482 (2000).

  27. 27

    Neish, A.S. et al. Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination. Science 289, 1560–1563 (2000).

  28. 28

    Guan, K.L. & Dixon, J.E. Eukaryotic proteins expressed in Escherichia coli: an improved thrombin cleavage and purification procedure of fusion proteins with glutathione S-transferase. Anal. Biochem. 192, 262–267 (1991).

  29. 29

    Shapiro, R., Weremowicz, S., Riordan, J.F. & Vallee, B.L. Ribonucleolytic activity of angiogenin: essential histidine, lysine, and arginine residues. Proc. Natl. Acad. Sci. USA 84, 8783–8787 (1987).

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Acknowledgements

We thank J. Dant for electron microscopy; S. Wagoner, C. Chen, D. O'Donnell and M. Karlsson for technical assistance; P. Cossart for providing Listeria strains; and M. Dunne for helpful suggestions. This work was supported by the NIH (DK30292 to J.I.G., DK02954 to T.S.S., and P30 DK52574 to L.V.H.), AstraZeneca (J.I.G.) and the Burroughs-Wellcome Fund (Career Award to L.V.H.).

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  1. Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, 63110, MO, USA

    • Lora V. Hooper
    • , Thaddeus S. Stappenbeck
    • , Chieu V. Hong
    •  & Jeffrey I. Gordon

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The authors declare no competing financial interests.

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Correspondence to Jeffrey I. Gordon.

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https://doi.org/10.1038/ni888

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