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Interferon-gamma Induces Melanogenesis Via Post-Translational Modification of Tyrosinase

Melanogenesis (melanin pigment production) in melanocytes is canonically stimulated by the alpha-melanocyte stimulating hormone (αMSH), which activates the cyclic-AMP-mediated expression of the melanocyte inducing transcription factor (MITF) and its downstream melanogenic genes, including the principal rate-limiting melanogenic enzyme tyrosinase (Tyr). Here we report that interferon-gamma (IFNG; type II interferon), but not IFN-alpha (a type I interferon), induces a noncanonical melanogenic pathway. Inhibition of IFNG pathway by the JAK inhibitor ruxolitinib or knocking out Stat1 abrogated the IFNG-induced melanogenesis. Interestingly, IFNG-induced melanogenesis was independent of MITF. IFNG markedly increased the Tyr protein expression but did not affect the mRNA expression, suggesting a post-translational regulatory mechanism. In contrast, IFNG had no effect on the expression of other melanogenesis-related proteins, e.g. tyrosinase-related protein 1 (Tyrp1) and dopachrome tautomerase (Dct). Glycosidase digestion assays revealed that IFNG treatment increased the mature glycosylated form of Tyr, but not its de novo synthesis. Moreover, cycloheximide chase assay showed that degradation of Tyr was decreased in IFNG-treated cells. These results suggest that the IFNG-STAT1 pathway regulates melanogenesis via modulation of the post-translational processing and protein stability of Tyr. SIGNIFICANCE The canonical pathway that controls melanogenesis in melanocytes is activated by the alpha melanocyte stimulating hormone (αMSH) via its receptor MC1R, which activates the cyclic-AMP-mediated expression of the melanocyte master regulator MITF and its downstream target genes involved in the melanogenic process. Here we report a novel non-canonical melanogenic pathway that is mediated via the Interferon-gamma cytokine signaling. We show that this non-canonical pathway is independent of MITF-mediated gene expression, but rather functions via post-translational modification of the principal melanogenic enzyme Tyrosinase.