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)

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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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