Interferon‐gamma induces melanogenesis via post‐translational regulation of tyrosinase. (20th March 2022)

• Record Type: Journal Article
• Authors: Mo, Xuan; Kazmi, Hasan Raza; Preston‐Alp, Sarah; Zhou, Bo; Zaidi, M. Raza
• Is Part Of: Pigment cell & melanoma research. Volume 35:Number 3(2022)
• Page Start: 342
• Page End: 355
• Publication Date: 2022-03-20
• Subjects: interferon‐gamma -- interferon‐gamma signaling -- melanin -- melanogenesis -- melanoma -- post‐translational modification -- tyrosinase; Melanoma -- Periodicals; Chromatophores -- Periodicals; Animal pigments -- Periodicals; 616.99477
• DOI: 10.1111/pcmr.13036
• Languages: English
• ISSNs: 1755-1471

Abstract

Abstract: 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 interferon‐alpha (a type I interferon), induces a noncanonical melanogenic pathway in mouse and human melanocytic cells. Inhibition of IFNG pathway by the JAK1/2 inhibitor ruxolitinib or knocking out Stat1 gene 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, for example, 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 regulation of the post‐translational processing and protein stability of TYR.