DEFA5

DEFA5 Full Name

defensin, alpha 5, Paneth cell-specific

DEFA5 Introduction

DEFA5 encodes a small cationic antimicrobial peptide belonging to the α-defensin subfamily of the defensin superfamily. The gene is located on chromosome 8p23.1, a locus that clusters with several other α-defensin family members. The mature HD-5 peptide is approximately 32 amino acids in length and is stabilized by three intramolecular disulfide bonds formed between six conserved cysteine residues, a structural hallmark shared across all α-defensins. This disulfide-bridged β-sheet architecture confers resistance to intestinal proteolysis and enables sustained activity in the lumen of the small intestine. DEFA5 expression is highly restricted to the Paneth cells of the small intestinal crypts of Lieberkühn, where it is synthesized as an inactive propeptide (pro-HD-5) and stored in electron-dense secretory granules. Upon stimulation by bacterial products such as lipopolysaccharide (LPS) or cholinergic signals, pro-HD-5 is secreted into the crypt lumen, where extracellular proteases — most notably the metalloproteinase matrilysin (MMP-7) — cleave the N-terminal propeptide to generate the fully active antimicrobial peptide.

Figure 1. Paneth cells in COVID-19. (Source: Cui C, et al. 2023)

The physiological role of DEFA5 extends beyond direct antimicrobial killing. By selectively eliminating bacterial pathogens while preserving commensal organisms, HD-5 acts as a critical regulator of the intestinal microbiome composition in the ileum. Transgenic mouse models overexpressing human HD-5 demonstrated profound shifts in the intestinal microbial community, confirming the dose-dependent impact of this peptide on the host–microbiome interface. Mechanistically, the cationic nature of mature HD-5 enables electrostatic interaction with negatively charged microbial membranes, leading to pore formation, membrane depolarization, and ultimately microbial lysis. Beyond bacteria, HD-5 exhibits activity against fungi and certain enveloped viruses, broadening its contribution to mucosal host defense.

The association between DEFA5 and human disease is best characterized in the context of inflammatory bowel disease (IBD). In patients with ileal Crohn's disease, the expression and secretion of Paneth cell α-defensins, including HD-5, are significantly reduced, resulting in compromised antimicrobial barrier function in the distal small intestine. This defensin deficiency facilitates dysbiotic shifts in the ileal microbiome and impairs bacterial clearance from intestinal crypts, potentially contributing to mucosal inflammation and perpetuating the chronic relapsing cycle of Crohn's disease. In contrast, HD-5 expression is paradoxically upregulated in the colon of patients with active IBD — including both ulcerative colitis and Crohn's colitis — attributable to the emergence of metaplastic Paneth cells, which are absent in normal colonic mucosa. This ectopic HD-5 expression in the inflamed colon may represent a compensatory innate immune response to sustained microbial challenge. Beyond IBD, DEFA5 overexpression has been observed in metaplastic gastric mucosa and some gastrointestinal cancers, suggesting that aberrant DEFA5 expression may serve as a marker of epithelial reprogramming in the gut.

Alternate Names for DEFA5

DEFA5; defensin, alpha 5, Paneth cell-specific; DEF5; HD-5; defensin-5; HD5(20-94); defensin 5; defensin, alpha 5, preproprotein;

• 1. Cui C, et al. Multifaceted involvements of Paneth cells in various diseases within intestine and systemically. Front Immunol. 2023 Mar 13;14:1115552.
  2. Cunliffe RN, et al. Human defensin 5 is stored in precursor form in normal Paneth cells and is expressed by some villous epithelial cells and by metaplastic Paneth cells in the colon in inflammatory bowel disease. Gut. 2001 Feb;48(2):176-85.