MC1R depalmitoylation inhibition reveals a physiological role for pheomelanin

Pheomelanin is a sulfur-containing pigment produced by melanocytes notably in individuals with red hair/fair skin and animals with orange integumentary structures. Pheomelanin is not photoprotective as the dark eumelanin, but is cytotoxic, being related to a high risk of melanoma independently of UV radiation. This questions any physiological role for the pigment. The persistence of genetic variants promoting pheomelanogenesis may be explained by a contribution to cysteine homeostasis, as the toxicity of excessive cysteine accumulation in melanocytes may be avoided when the amino acid is used to build the inert pigment. Such function remains untested. Recently, melanocortin-1 receptor (MC1R) signaling, which hinders pheomelanogenesis, has been shown to be highly dependent on its degree of palmitoylation. Finding an efficient selective inhibitor of the enzyme that catalyzes depalmitoylation (APT2), ML349, has thus opened a convenient pharmacological method to block pheomelanogenesis and thus test for its physiological role. Here, a simultaneous treatment with dietary cysteine and ML349 impaired feather pheomelanin-based pigmentation in male zebra finches <i>Taeniopygia guttata</i>. ML349 treatment resulted in the increase in systemic oxidative damage (malondialdehyde) when accounting for the antioxidant capacity of orange, pheomelanin-producing follicular melanocytes by means of <i>NFE2L2</i> expression, but not that of black, eumelanin-producing melanocytes. Females, that do not produce pheomelanin, were not affected by ML349, but cysteine supplementation tended to increase their oxidative damage. These findings prove a role of pheomelanin in cysteine homeostasis, opening a better understanding of melanoma risk through environmental factors affecting cysteine availability, and the evolutionary predictors of animal color diversity.