Pigmentation and TYRP1 expression are mediated by zinc through the early secretory pathway-resident ZNT proteins

Tyrosinase (TYR) and tyrosinase-related proteins 1 and 2 (TYRP1 and TYRP2) are essential for pigmentation. They are generally classified as type-3 copper proteins, with binuclear copper active sites. Although there is experimental evidence for a copper cofactor in TYR, delivered via the copper transporter, ATP7A, the presence of copper in TYRP1 and TYRP2 has not been demonstrated. Here, we report that the expression and function of TYRP1 requires zinc, mediated by ZNT5-ZNT6 heterodimers (ZNT5-6) or ZNT7-ZNT7 homodimers (ZNT7). Loss of ZNT5-6 and ZNT7 function results in hypopigmentation in medaka fish and human melanoma cells, and is accompanied by immature melanosomes and reduced melanin content, as observed in TYRP1 dysfunction. The requirement of ZNT5-6 and ZNT7 for TYRP1 expression is conserved in human, mouse, and chicken orthologs. Our results provide novel insights into the pigmentation process and address questions regarding metalation in tyrosinase protein family. Zinc transporters ZNT5-6 and ZNT7 are essential for pigmentation and for the expression and function of tyrosinase-related protein TYRP1 in human melanoma cells and medaka fish.

Automated summary

Zinc transporters ZNT5-6 and ZNT7 are necessary for pigmentation and the expression and function of tyrosinase-related protein TYRP1 in human melanoma cells and medaka fish. Loss of ZNT5-6 and ZNT7 function leads to hypopigmentation, immature melanosomes, and reduced melanin content, similar to TYRP1 dysfunction. The requirement of ZNT5-6 and ZNT7 for TYRP1 expression is conserved in human, mouse, and chicken orthologs.