Beclin 1 controls pigmentation by changing the nuclear localization of melanogenic factor MITF

The primary contributor for the determination of skin color is melanin, a pigment that is produced in specialized cells called melanocytes. At cellular level, melanin synthesis occurs through several enzymes like tyrosinase (TYR) and tyrosinase related proteins and the expression of these proteins are regulated transcriptionally by microphthalmia associated transcription factor (MITF). Melanin pigmentation is a complex process finely regulated by different transcription factors, structural proteins and enzymes. In recent times, several autophagic genes have been implicated in the regulation of pigmentation. Though previous report observed a visible loss of coat-color in heterozygous Beclin 1 mice, the role of this protein in pigmentation is yet to study in details. In this present work we intend to study the role of Beclin 1, a central autophagic factor, in pigmentation. Using human melanoma cells and primary melanocytes, we showed that Beclin 1 downregulation significantly decreased the melanin content, tyrosinase activity and the expression of TYR and tyrosinase related protein 1 (TYRP1). These effects were recapitulated in a Beclin 1 knockdown in vivo model of zebrafish. Most importantly, re-expression of Beclin 1 rescued the pigmentation-associated defects both in cellular and in organismal level indicating the specificity. Surprisingly, Beclin 1 knockdown cells did not show significant changes in MITF expression but the nuclear localization of MITF was altered. Together, these data suggest that indeed Beclin 1 is associated with melanogenesis and this effect is more likely exerted through the subcellular distribution rather than the change in expression of MITF.