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Paneth cell trypsin is the processing enzyme for human defensin-5

Nature Immunology volume 3, pages 583–590 (2002)Cite this article

Abstract

The antimicrobial peptide human α-defensin 5 (HD5) is expressed in Paneth cells, secretory epithelial cells in the small intestine. Unlike other characterized defensins, HD5 is stored in secretory vesicles as a propeptide. The storage quantities of HD5 are ∼90–450 μg per cm2 of mucosal surface area, which is sufficient to generate microbicidal concentrations in the intestinal lumen. HD5 peptides isolated from the intestinal lumen are proteolytically processed forms—HD5(56–94) and HD5(63–94)—that are cleaved at the Arg55-Ala56 and Arg62-Thr63 sites, respectively. We show here that a specific pattern of trypsin isozymes is expressed in Paneth cells, that trypsin colocalizes with HD5 and that this protease can efficiently cleave HD5 propeptide to forms identical to those isolated in vivo. By acting as a prodefensin convertase in human Paneth cells, trypsin is involved in the regulation of innate immunity in the small intestine.

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Figure 1: Analysis of tissue and lumenal forms of HD5.
Figure 2: Primary structure of preproHD5 deduced from the cDNA sequence24.
Figure 3: Antibacterial activity of HD5 peptides.
Figure 4: In vitro cleavage of proHD5 by trypsin.
Figure 5: Expression of trypsin in Paneth cells.
Figure 6: Analysis of trypsin isoform expression in human pancreas and ileum.

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Acknowledgements

We thank members of the CCF Center for Inflammatory Bowel Diseases—especially B. Lashner, J.-P. Achkar, V. Fazio and S. Strong—for obtaining tissue specimens used in this study. Some tissue samples were provided by the Cooperative Human Tissue Network, which is funded by the National Cancer Institute. We thank J. S. Lee and W. Wu for excellent assistance, and members of the Ganz and Bevins laboratories and K. Singh Aulak for helpful discussions. Supported by grants from the NIH (AI32738 to C. L. B., HL46809 to T. G. and EY06603 to J. W. C.).

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Authors and Affiliations

  1. Department of Immunology, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, 44195, OH, USA

    Dipankar Ghosh, Bo Shen, Sarah K. Lee, Dennis Wilk & Charles L. Bevins

  2. The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, 44195, OH, USA

    Dipankar Ghosh, Sarah K. Lee, Dennis Wilk, Judith Drazba, Satya P. Yadav, John W. Crabb & Charles L. Bevins

  3. Department of Medicine, UCLA School of Medicine, 10833 Le Conte Ave., Los Angeles, 90095, CA, USA

    Edith Porter & Tomas Ganz

  4. Department of Biological Sciences, California State University, 5151 State University Dr., Los Angeles, 90032, CA, USA

    Edith Porter

  5. Department of Gastroenterology, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, 44195, OH, USA

    Bo Shen & Charles L. Bevins

  6. The Cole Eye Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, 44195, OH, USA

    John W. Crabb

  7. Department of Colorectal Surgery, The Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, 44195, OH, USA

    Charles L. Bevins

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Ghosh, D., Porter, E., Shen, B. et al. Paneth cell trypsin is the processing enzyme for human defensin-5. Nat Immunol 3, 583–590 (2002). https://doi.org/10.1038/ni797

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