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

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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Figure 1: Tissue-specific patterns of expression of mouse angiogenin family members.
Figure 2: Ang4 localizes to Paneth cell secretory granules and is secreted in response to LPS.
Figure 3: Mouse and human angiogenins exhibit species-selective microbicidal activity.
Figure 4: Ang4 expression is induced by normal intestinal bacteria.

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References

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

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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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Correspondence to Jeffrey I. Gordon.

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Hooper, L., Stappenbeck, T., Hong, C. et al. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nat Immunol 4, 269–273 (2003). https://doi.org/10.1038/ni888

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