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The CNC-family transcription factor Nrf3 coordinates the melanogenesis cascade through macropinocytosis and autophagy regulation

Melanin is a pigment produced from the amino acid L-tyrosine in melanosomes. The CNC-family transcription factor Nrf3 is expressed in the basal layer of the epidermis, where melanocytes reside, but its melanogenic function is unclear. Here, we show that Nrf3 regulates macropinocytosis and autophagy to coordinate melanogenesis cascade. In response to an exogenous inducer of melanin production, forskolin, Nrf3 upregulates the core melanogenic gene circuit, which includes Mitf, Tyr, Tyrp1, Pmel, and Oca2. Furthermore, Nrf3 induces the gene expression of Cln3, an autophagosome-related factor, for melanin precursor uptake by macropinocytosis. Ulk2 and Gabarapl2 are also identified as Nrf3-target autophagosome-related genes for melanosome formation. In parallel, Nrf3 prompts autolysosomal melanosome degradation for melanocyte survival. An endogenous melanogenic inducer αMSH also activates Nrf3-mediated melanin production, whereas it is suppressed by an HIV-1 protease inhibitor, nelfinavir. These findings indicate the significant role of Nrf3 in the melanogenesis and the anti-melanogenic potential of nelfinavir.

 

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Based on the research mentioned, it appears that the transcription factor Nrf3 plays a crucial role in regulating melanogenesis, the process by which melanocytes produce the pigment melanin. Specifically, Nrf3 is involved in coordinating the various steps of the melanogenesis cascade, including melanin precursor uptake, autophagy, macropinocytosis, and melanosome formation and degradation.

In response to an external inducer of melanin production, forskolin, Nrf3 activates the core melanogenic gene circuit, which includes Mitf, Tyr, Tyrp1, Pmel, and Oca2. In addition, Nrf3 induces the expression of Cln3, a gene involved in autophagosome formation and melanin precursor uptake through macropinocytosis.

Nrf3 also targets autophagosome-related genes such as Ulk2 and Gabarapl2 for melanosome formation, and it prompts autolysosomal melanosome degradation for melanocyte survival. Moreover, the study indicates that an endogenous melanogenic inducer, αMSH, also activates Nrf3-mediated melanin production, while it is inhibited by an HIV-1 protease inhibitor, nelfinavir, indicating the potential anti-melanogenic effect of this drug.

Overall, these findings suggest that Nrf3 plays a critical role in melanogenesis by regulating autophagy and macropinocytosis for melanin precursor uptake and melanosome formation and degradation, respectively. The study also highlights the potential therapeutic implications of targeting Nrf3 for the treatment of hyperpigmentation disorders or as a potential anti-melanogenic target in HIV-1 infected individuals taking nelfinavir.

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