Alternative titles; symbolsDEFB103HBD3HBP3DEFENSIN, BETA, 3, FORMERLY; DEFB3, FORMERLYHGNC Approved Gene Symbol: DEFB103BCytogenetic location: 8p23.1 Genomic...
Alternative titles; symbols
HGNC Approved Gene Symbol: DEFB103B
Cytogenetic location: 8p23.1 Genomic coordinates (GRCh38): 8:7,428,887-7,430,347 (from NCBI)
Two classes of defensins, alpha and beta, differ in their disulfide bond pairing, genomic organization, and tissue distribution. Alpha-defensins are expressed in neutrophils (e.g., DEFA1, 125220) and in Paneth cells and other epithelia (e.g., DEFA5, 600472), and beta-defensins are expressed in epithelia (e.g., DEFB1, 602056). Epithelial beta-defensins are broad-spectrum cationic antimicrobial peptides. They may also act as chemokines for immature dendritic cells and memory T cells via CCR6 (601835), bridging the innate and adaptive immune systems. DEFB103 belongs to the beta class of defensins (Jia et al., 2001).
▼ Cloning and Expression
By screening a BAC library spanning the defensin locus on chromosome 8p23-p22 for sequences similar to that of DEFB2 (602215), Jia et al. (2001) identified a cDNA encoding the DEFB3 protein, which they designated HBD3. The predicted 67-amino acid DEFB3 protein is 43% identical to DEFB2 and has the 6-cysteine motif typical of beta-defensins. PCR analysis of cDNA panels revealed expression in adult heart, skeletal muscle, and placenta as well as in fetal thymus. RNA dot blot analysis detected expression most readily in esophagus.
Independently, by biochemical purification of psoriatic lesional scale extracts containing high anti-Staphylococcus aureus activity, followed by N-terminal microsequence analysis and screening of a keratinocyte cDNA library by PCR with degenerate primers, Harder et al. (2001) also cloned a cDNA encoding DEFB3. Electrospray mass spectrometric analysis indicated that DEFB3 is a 5.15-kD protein. RT-PCR analysis detected strongest expression of DEFB3 in skin and tonsils, as well as in primary keratinocytes and epithelial cells.
▼ Gene Function
Jia et al. (2001) found that IL1B (147720) stimulated expression of DEFB3 in fetal lung tissue.
Functional analysis by Harder et al. (2001) showed that recombinant DEFB3 has salt-insensitive activity against a range of pathogenic gram-positive organisms equivalent to the natural product obtained from psoriatic tissue or normal heal callus. Transmission electron microscopy suggested that DEFB3 perforates the peripheral cell wall of S. aureus prior to explosive liberation of the plasma membrane and bacteriolysis. DEFB3 did not induce hemolysis of erythrocytes at physiologic salt concentrations and only had hemolytic activity at high peptide concentrations in the presence of sucrose. Inflammatory stimuli upregulated DEFB3 in epithelial cells. Harder et al. (2001) proposed that DEFB3 may be part of novel strategies to deal with skin and respiratory tract infections, including those related to cystic fibrosis (219700).
Using healthy human skin fragments obtained as surgical residua, Sorensen et al. (2006) demonstrated that sterile wounding of human skin induces epidermal expression of the antimicrobial polypeptides DEFB103, lipocalin-2 (LCN2; 600181), and secretory leukocyte protease inhibitor (SLPI; 107285) through activation of EGFR (131550) by heparin-binding EGF (HBEGF; 126150). Studies in epidermal cultures showed that activation of EGFR generated antimicrobial concentrations of DEFB103 and increased activity of the cultures against Staphylococcus aureus. Sorensen et al. (2006) concluded that sterile wounding initiates an innate immune response that increases resistance to overt infection and microbial colonization.
Feng et al. (2006) found that HBD3 not only blocked human immunodeficiency virus (HIV)-1 replication via direct interaction with virions and modulation of the CXCR4 (162643) coreceptor, but it also competed with the CXCR4 ligand, SDF1 (CXCL12; 600835), and promoted internalization of CXCR4 without inducing calcium flux, ERK (see MAPK3; 601795) phosphorylation, or chemotaxis. HBD3 had no effect on other G protein-coupled receptors (e.g., CCR5; 601373). Feng et al. (2006) proposed that HBD3 or its derivatives may have potential for HIV and/or immunoregulatory therapy.
Funderburg et al. (2007) showed that HBD3 induced expression of the costimulatory molecules CD80 (112203), CD86 (601020), and CD40 (109535) on monocytes by interacting with both TLR1 (601194) and TLR2 (603028). Signaling required MYD88 (602170) and resulted in IRAK1 (300283) phosphorylation. Funderburg et al. (2007) concluded that TLR signaling can be induced by host-derived peptides, such as HBD3, as well as by microbial patterns.
▼ Gene Structure
On the basis of genomic sequence analysis, Jia et al. (2001) estimated that the DEFB3 gene contains at least 2 exons. Promoter analysis detected consensus sequences for multiple inflammatory response elements, but no NFKB (see 164011) consensus elements.
The DEFB3 gene maps to 8p23-p22, by merit of its inclusion within a BAC spanning the defensin cluster at that location (Jia et al., 2001). The DEFB3 gene is located approximately 13 kb upstream from the DEFB2 gene, and HE2 (SPAG11; 606560) is located another 17 kb farther upstream. All 3 of these genes are transcribed in the same direction.
▼ Animal Model
In most vertebrates, 2 key genes, agouti (600201) and melanocortin-1 receptor (MC1R; 155555), encode a ligand-receptor system that controls pigment 'type switching' (switching between the synthesis of eumelanin and pheomelanin), but in domestic dogs, a third gene is involved, the K locus, whose genetic characteristics predicted an unrecognized component of the melanocortin pathway. Candille et al. (2007) identified the K locus as beta-defensin-103 and showed that its protein product binds with high affinity to MC1R and has a simple and strong effect on pigment type switching in domestic dogs and transgenic mice. Candille et al. (2007) concluded that their results expanded the functional role of beta-defensins, a protein family previously implicated in innate immunity, and identified an additional class of ligands for signaling through melanocortin receptors.
Melanism in the gray wolf, Canis lupus, is caused by mutation in the K locus, which encodes a beta-defensin protein that acts as an alternative ligand for Mc1r. Anderson et al. (2009) showed that the melanistic K locus mutation in North American wolves derives from past hybridization with domestic dogs, has risen to high frequency in forested habitats, and exhibits a molecular signature of positive selection. The same mutation also causes melanism in the coyote, Canis latrans, and in Italian gray wolves. Anderson et al. (2009) concluded that their results demonstrated how traits selected in domesticated species can influence the morphologic diversity of their wild relatives.