MART-1 Is Required for the Function of the Melanosomal Matrix Protein PMEL17/GP100 and the Maturation of Melanosomes

Toshihiko Hoashi,Hidenori Watabe,Jacqueline Muller,Yuji Yamaguchi,Wilfred D Vieira,Vincent J Hearing

doi:10.1074/jbc.m413692200

Toshihiko Hoashi, Hidenori Watabe + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m413692200

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Abstract

More than 125 genes that regulate pigmentation have been identified to date. Of those, MART-1 has been widely studied as a melanoma-specific antigen and as a melanosome-specific marker. Whereas the functions of other melanosomal proteins, such as tyrosinase, tyrosinase-related protein-1, dopachrome tautomerase, and Pmel17, are known, the function of MART-1 in melanogenesis, is unclear. A role for MART-1 in pigmentation is expected because its expression pattern and subcellular distribution is quite similar to the other melanosomal proteins and usually correlates with melanin content. We investigated the function of MART-1 using a multidisciplinary approach, including the use of siRNA to inhibit MART-1 function and the use of transfection to re-express MART-1 in MART-1-negative cells. We show that MART-1 forms a complex with Pmel17 and affects its expression, stability, trafficking, and the processing which is required for melanosome structure and maturation. We conclude that MART-1 is indispensable for Pmel17 function and thus plays an important role in regulating mammalian pigmentation.

Highlights

(TYR),1 tyrosinase-related protein-1 (TYRP1), dopachrome tautomerase (DCT), Pmel17, and MART-1 are well known as melanosome-specific proteins, and, with the exception of MART-1, all have specific and defined roles in melanogenesis
MART-1 has no apparent homology to other known melanosomal proteins and no detectable enzymatic activity, MART-1 is highly enriched in early melanosomes (Stage I and/or II melanosomes) [5, 10], which suggests that it might play some role in early melanogenesis and may be trafficked to melanosomes with other melanosomal proteins
We characterized the expression of various other melanosomal proteins, including TYR, TYRP1, DCT, and Pmel17, in those four types of cells; all four types of cells expressed TYR, DCT, and Pmel17 (Fig. 1A)

Summary

Introduction

(TYR), tyrosinase-related protein-1 (TYRP1), dopachrome tautomerase (DCT), Pmel, and MART-1 ( known as Melan-A) are well known as melanosome-specific proteins, and, with the exception of MART-1, all have specific and defined roles in melanogenesis. MART-1 was initially cloned by two independent groups using melanoma reactive CD8ϩ T cells [8, 9]. Pmel was cloned initially as a melanoma specific antigen recognized by tumor infiltrating lymphocytes [14]. Both MART-1 and Pmel serve as common targets for tumordirected T lymphocytes; both are often highly expressed in melanoma cells and have been widely studied as targets of immunotherapy for melanoma [15]. This study provides important clues toward understanding the synergistic effects of melanosomeassociated proteins and the role of MART-1 in pigmentation

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