DEFA5 explained

Defensin, alpha 5 (DEFA5) also known as human alpha defensin 5 (HD5) is a protein that in humans is encoded by the DEFA5 gene.^[1] DEFA5 is expressed in the Paneth cells of the ileum.^[2]

Defensins are a family of microbicidal and cytotoxic peptides (antimicrobial peptides; AMP) that are involved in host defense, and help to maintain homeostasis of intestinal microbiota. DEFA5 is the main AMP that controls the enteric microbiota composition by selective killing of bacterial pathogens while preserving commensals.^[3]

Structure

Defensins are small cationic peptides linked via three intra-molecular disulfide bridges, and contain six intra-molecular cysteine residues which form an unalterable and specific pattern of disulfide bridges which protects them from proteolysis and maintains function in the intestinal lumen.^{[4] [5]} Members of the defensin family are highly similar in protein sequence and distinguished by a conserved cysteine motif.

Gene and tissue distribution

Several of the human alpha defensin genes appear to be clustered on chromosome 8. The protein encoded by this gene, α-defensin-5, is highly expressed in the secretory granules of Paneth cells of the ileum.^[6]

Function

In addition to antimicrobial activity, inactivation and neutralization of several bacterial toxins, especially an inhibitory potency against Clostridioides difficile toxins were reported.^{[7] [8]} α-defensin-5 is able to inhibit all three C. difficile toxins A (TcdA), B (TcdB) and CDT in the concentration-dependent manner, and inhibitory mechanism is different for each of them. TcdA and TcdB are inhibited by co-precipitation with DEFA5, and CDT is inhibited by the inactivation of the CDTb pore.^[9] In addition to toxin neutralization, DEFA5 is capable to directly kill C. difficile cells by damaging the bacterial wall^[10]

Further reading

• Mallow EB, Harris A, Salzman N, Russell JP, DeBerardinis RJ, Ruchelli E, Bevins CL . Human enteric defensins. Gene structure and developmental expression . The Journal of Biological Chemistry . 271 . 8 . 4038–45 . February 1996 . 8626737 . 10.1074/jbc.271.8.4038 . free .
• Bevins CL, Jones DE, Dutra A, Schaffzin J, Muenke M . Human enteric defensin genes: chromosomal map position and a model for possible evolutionary relationships . Genomics . 31 . 1 . 95–106 . January 1996 . 8808285 . 10.1006/geno.1996.0014 .
• Porter EM, Liu L, Oren A, Anton PA, Ganz T . Localization of human intestinal defensin 5 in Paneth cell granules . Infection and Immunity . 65 . 6 . 2389–95 . June 1997 . 9169779 . 175331 . 10.1128/IAI.65.6.2389-2395.1997 .
• Quayle AJ, Porter EM, Nussbaum AA, Wang YM, Brabec C, Yip KP, Mok SC . Gene expression, immunolocalization, and secretion of human defensin-5 in human female reproductive tract . The American Journal of Pathology . 152 . 5 . 1247–58 . May 1998 . 9588893 . 1858596 .
• Ghosh D, Porter E, Shen B, Lee SK, Wilk D, Drazba J, Yadav SP, Crabb JW, Ganz T, Bevins CL . 6 . Paneth cell trypsin is the processing enzyme for human defensin-5 . Nature Immunology . 3 . 6 . 583–90 . June 2002 . 12021776 . 10.1038/ni797 . 22022089 .
• Salzman NH, Ghosh D, Huttner KM, Paterson Y, Bevins CL . Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin . Nature . 422 . 6931 . 522–6 . April 2003 . 12660734 . 10.1038/nature01520 . 2003Natur.422..522S . 1096692 .
• Szyk A, Wu Z, Tucker K, Yang D, Lu W, Lubkowski J . Crystal structures of human alpha-defensins HNP4, HD5, and HD6 . Protein Science . 15 . 12 . 2749–60 . December 2006 . 17088326 . 2242434 . 10.1110/ps.062336606 .
• Wu Z, Ericksen B, Tucker K, Lubkowski J, Lu W . Synthesis and characterization of human alpha-defensins 4-6 . The Journal of Peptide Research . 64 . 3 . 118–25 . September 2004 . 15317502 . 10.1111/j.1399-3011.2004.00179.x .
• de Leeuw E, Burks SR, Li X, Kao JP, Lu W . Structure-dependent functional properties of human defensin 5 . FEBS Letters . 581 . 3 . 515–20 . February 2007 . 17250830 . 1832120 . 10.1016/j.febslet.2006.12.036 .

Notes and References

1. Jones DE, Bevins CL . Defensin-6 mRNA in human Paneth cells: implications for antimicrobial peptides in host defense of the human bowel . FEBS Letters . 315 . 2 . 187–92 . January 1993 . 8417977 . 10.1016/0014-5793(93)81160-2 . 45099115 . free .
2. Zhao C, Wang I, Lehrer RI . Widespread expression of beta-defensin hBD-1 in human secretory glands and epithelial cells . FEBS Letters . 396 . 2–3 . 319–22 . November 1996 . 8915011 . 10.1016/0014-5793(96)01123-4 . 22367037 . free .
3. Bevins CL, Salzman NH . Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis . Nature Reviews. Microbiology . 9 . 5 . 356–68 . May 2011 . 21423246 . 10.1038/nrmicro2546 . 39332656 .
4. Ganz T, Lehrer RI . Defensins . Current Opinion in Immunology . 6 . 4 . 584–9 . August 1994 . 7946046 . 10.1016/0952-7915(94)90145-7 .
5. Selsted ME, Harwig SS . Determination of the disulfide array in the human defensin HNP-2. A covalently cyclized peptide . The Journal of Biological Chemistry . 264 . 7 . 4003–7 . March 1989 . 10.1016/S0021-9258(19)84952-9 . 2917986 . free .
6. Web site: Entrez Gene: DEFA5 defensin, alpha 5, Paneth cell-specific.
7. Kim C, Slavinskaya Z, Merrill AR, Kaufmann SH . Human alpha-defensins neutralize toxins of the mono-ADP-ribosyltransferase family . The Biochemical Journal . 399 . 2 . 225–9 . October 2006 . 16817779 . 1609915 . 10.1042/BJ20060425 .
8. Giesemann T, Guttenberg G, Aktories K . Human alpha-defensins inhibit Clostridium difficile toxin B . Gastroenterology . 134 . 7 . 2049–58 . June 2008 . 18435932 . 10.1053/j.gastro.2008.03.008 . free .
9. Korbmacher M, Fischer S, Landenberger M, Papatheodorou P, Aktories K, Barth H . Human α-Defensin-5 Efficiently Neutralizes Clostridioides difficile Toxins TcdA, TcdB, and CDT . Frontiers in Pharmacology . 11 . 1204 . 2020 . 32903430 . 7435013 . 10.3389/fphar.2020.01204 . free .
10. Furci L, Baldan R, Bianchini V, Trovato A, Ossi C, Cichero P, Cirillo DM . New role for human α-defensin 5 in the fight against hypervirulent Clostridium difficile strains . Infection and Immunity . 83 . 3 . 986–95 . March 2015 . 25547793 . 4333456 . 10.1128/IAI.02955-14 . Morrison RP .