Of special interest to Zalfa Abdel-Malik, melanocyte cells in the skin and hair follicles make a pigment called melanin, and these cells can give rise to the deadly skin cancer melanoma. Melanin protects the skin against ultraviolet (UV) radiation from sunlight, which are able to cause DNA damage including harmful mutations. The type of this pigment made by melanocytes is controlled by the melanocortin-1 receptor (MC1R) protein. MC1R up-regulation results in production of a dark form of melanin called eumelanin; however, if MC1R signalling is low or absent, the primary type of melanin that is produced is a red or orange form called phaeomelanin. Virtually all red-haired individuals have a version of MC1R with diminished or absent signaling capacity, and most of these individuals have fair skin that doesn’t tan easily.
The Mc1r gene was first identified in mice in which a loss-of-function mutation of the gene causes yellow fur. Many other species (e.g. dogs with red or yellow hair) also have pigment alterations associated with specific versions of MC1R. Humans of ancient European ancestry often have variant forms of MC1R, which differ in the level of their association with red hair. MC1R variation is necessary, but not always sufficient, to produce red hair –– suggesting that most variants retain some signaling activity that may be masked or enhanced, depending on modifier genes or other cellular factors. In the attached article and editorial, authors studied mouse models and human cells showing that risk of skin cancer associated with certain versions of MC1R, linked to red hair, can be lowered by increasing the degree to which this protein is modified by a lipid.
Authors screened human melanocytes grown in cell culture and identified palmitate as a lipid molecule that enhances downstream MC1R signaling –– in mutant MC1R proteins associated with red hair. Moreover, red and yellow dogs that lack MC1R signaling were found to have a mutation that removes the palmitate-binding site from the protein, suggesting this site might be important for MC1R function. Authors then showed that MC1R is palmitoylated in human cells grown in culture, and that the degree of palmitoylation increases in response to UV treatment and stimulation of the receptor by the peptide hormone α-MSH (a protein produced by nearby keratinocyte cells after UV damage). Rises in the level of palmitoylation of MC1R led to an increase in MC1R-mediated signaling and activation of the melanin-production pathway. Authors also tested an MC1R variant (in mice that are yellow, indicating absence of MC1R function) that cannot be palmitoylated; this receptor lacked signaling activity, whether or not it was stimulated by UV light. This elegant study therefore highlights a central role for MC1R palmitoylation in pigmentation and protection against melanoma.
Nature 21 Sept 2o17; 549: 399–403 and News’N’Views editorial pp 337–339