Skin pigmentation is essential to balance skin cancer risk and vitamin D production. Ultraviolet light, and specific gene expression patterns, determine skin color via regulation of pheomelanin and eumelanin levels. However, the exact underlying mechanisms are unclear. Here, we describe a novel conserved mechanism of skin pigmentation in which intramelanosomal redox changes impact protein degradation of ubiquitin-proteasome system-mediated tyrosinase, changing the eumelanin and pheomelanin levels in vitro, ex vivo and in vivo. One of the proteins involved in this process is nicotinamide nucleotide transhydrogenase (NNT). Targeting the NNT enzyme with topical small-molecule inhibitors yielded striking skin darkening. In addition, zebrafish overexpressing NNT displayed decreased pigmentation, and mice with decreased NNT function displayed increased pigmentation. To investigate whether NNT gene variations impact skin color variation in human populations, we performed association analysis in four cohorts with different continental ancestries and totaling up to 57,624 individuals and found significant associations between skin color and two single nucleotide polymorphisms in and close to NNT, as well as an association with the risk to sunburn. Skin of patients with postinflammatory hyperpigmentation, melasma and lentigines displayed decreased NNT expression levels, emphasizing the clinical relevance of this mechanism. These results suggest the existence of a redox-dependent pigmentation mechanism, affecting human tyrosinase protein stability, which can be modified by changing NNT enzyme activity. Application of NNT-modifying topical drugs might be used for medical and cosmetic purposes, as well as potential skin cancer prevention strategies.

Identifying a novel mechanism of human skin pigmentation