PERSPECTIVES

-Defensins are antimicrobial peptides of key interest be-cause they operate in both innate and adaptive immune responses in mammals (1). Now, these peptides have become more intriguing. On page 1418 of this issue, Candille et al. (2) identify a role for a β-defensin in pigmenta-tion. The peptide, CBD103, binds to melanocortin 1 receptor, one of a protein family that controls pig-mentation, inflammation, and feed-ing behavior. This expands the functional repertoire of β-defensins and opens new avenues of research with potential implications for human disease (see the figure). How does a gene implicated in mammalian immune responses alter pigmentation? A mutation at the KB locus was identified as the cause of dominant inheritance of a black coat in dogs (3). Candille et al. identify the gene at this locus as CBD103, the dog ortholog of human DEFB103, which encodes the β-defensin HBD3. The KB mutation results in loss of the predicted first amino acid of mature CBD103. Mutant CBD103 is more efficiently secreted from cells and has a higher affinity than the wild-type peptide for the dog melanocortin 1 receptor, which controls production of eume-lanin, the black/brown hair pigment. CBD103 also competes with agouti signal-ing protein for binding to this receptor. Agouti signaling protein antagonizes the melanocortin 1 receptor, resulting in the production of pheo-melanin, a red/yellow pigment. Wild-type and mutant CBD103 suppressed agouti signaling protein in transgenic mice, resulting in black hair rather than agouti (hair with a yellow stripe). A reasonable conclusion is that in-creased abundance and stronger affinity for the melanocortin 1 receptor allows mutant β-defensin to competitively inhibit agouti sig-naling protein in melanocytes, enabling the production of eumelanin and black hair. There is a conundrum, as the β-defensin also competes with α-melanocyte–stimulating hormone (a melanocortin) to bind melano-cortin 1 receptor, yet it does not itself elicit adenosine 3´, 5´-monophosphate signaling that characterizes this receptor’s activation. So how does this receptor elicit black pigment production in response to CBD103? Perhaps the dog receptor has ligand-independent sig-naling, as seen in the mouse (but not human), in which lack of α-melanocyte-stimulating hormone has little effect on pigmentation (4)