1. β-Defensin 19/119 mediates sperm chemotaxis and is associated with idiopathic infertility
Xiaofeng Li, et al. Cell Rep Med. 2022 Dec 20;3(12):100825. doi: 10.1016/j.xcrm.2022.100825. Epub 2022 Dec 12.
Sperm chemotaxis is required for guiding sperm toward the egg. However, the molecular identity of physiological chemoattractant and its involvement in infertility remain elusive. Here, we identify DEFB19/119 (mouse/human orthologs) as a physiological sperm chemoattractant. The epithelia of the female reproductive tract and the cumulus-oocyte complex secrete DEFB19/119 that elicits calcium mobilization via the CatSper channel and induces sperm chemotaxis in capacitated sperm. Manipulating the level of DEFB19 in mice determines the number of sperm arriving at the fertilization site. Importantly, we identify exon mutations in the DEFB119 gene in idiopathic infertile women with low level of DEFB119 in the follicular fluid. The level of DEFB119 correlates with the chemotactic potency of follicular fluid and predicts the infertile outcome with positive correlation. This study reveals the pivotal role of DEFB19/119 in sperm chemotaxis and demonstrates its potential application in the diagnosis of idiopathic infertility.
2. Solution structure of bovine neutrophil beta-defensin-12: the peptide fold of the beta-defensins is identical to that of the classical defensins
G R Zimmermann, P Legault, M E Selsted, A Pardi Biochemistry. 1995 Oct 17;34(41):13663-71. doi: 10.1021/bi00041a048.
The solution structure is reported for bovine neutrophil beta-defensin-12 (BNBD-12), a member of the beta-defensin family of antimicrobial peptides. Structural constraints in the form of proton-proton distances, dihedral angles, and hydrogen bond constraints were derived from two-dimensional, homonuclear magnetic resonance spectroscopy experiments. The three-dimensional structure of BNBD-12 was calculated using distance geometry and restrained molecular dynamics. An ensemble of structures with low NOE constraint violation energies revealed a precisely defined triple-stranded, antiparallel beta-sheet as the structural core of the peptide. The N-terminal beta-strand and three locally well-defined tight turns form a hydrophobic face. Conserved isoleucine and glycine residues form a beta-bulge structure which initiates a beta-hairpin secondary structure motif composed of the second and C-terminal beta-strands. The beta-hairpin contains numerous charged residues and forms the cationic face of BNBD-12. The N-terminal residues were found to be disordered, due to an absence of tertiary NOEs. The triple-stranded beta-sheet, the beta-bulge preceding the hairpin, and the cationic/hydrophobic amphiphilic character are definitive features of all defensin structures determined to date. Further, we predict that the tracheal antimicrobial peptide (TAP) and the recently described gallinacins will have tertiary structures similar to that of BNBD-12.
3. The Antimicrobial Peptide Human β-Defensin-3 Accelerates Wound Healing by Promoting Angiogenesis, Cell Migration, and Proliferation Through the FGFR/JAK2/STAT3 Signaling Pathway
Miho Takahashi, et al. Front Immunol. 2021 Sep 14;12:712781. doi: 10.3389/fimmu.2021.712781. eCollection 2021.
In addition to its antimicrobial activity, the skin-derived antimicrobial peptide human β-defensin-3 (hBD-3) promotes keratinocyte proliferation and migration to initiate the wound healing process; however, its effects on fibroblasts, which are the major cell type responsible for wound healing, remain unclear. We investigated the role of hBD-3 in cell migration, proliferation and production of angiogenic growth factors in human fibroblasts and evaluated the in vivo effect of hBD-3 on promoting wound healing and angiogenesis. Following hBD-3 treatment, the mouse wounds healed faster and showed accumulation of neutrophils and macrophages in the early phase of wound healing and reduction of these phagocytes 4 days later. hBD-3-treated wounds also displayed an increased number of fibroblasts and newly formed vessels compared to those of the control mice. Furthermore, the expression of various angiogenic growth factors was increased in the hBD-3-treated wounds. Additionally, in vitro studies demonstrated that hBD-3 enhanced the secretion of angiogenic growth factors such as fibroblast growth factor, platelet-derived growth factor and vascular endothelial growth factor and induced the migration and proliferation of human fibroblasts. The hBD-3-mediated activation of fibroblasts involves the fibroblast growth factor receptor 1 (FGFR1)/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathways, as evidenced by the inhibitory effects of pathway-specific inhibitors. We indeed confirmed that hBD-3 enhanced the phosphorylation of FGFR1, JAK2 and STAT3. Collectively, the current study provides novel evidence that hBD-3 might be a potential candidate for the treatment of wounds through its ability to promote wound healing, angiogenesis and fibroblast activation.
