The AhR-TFAP2A Axis Regulates Melanosome Transport by Directly Targeting Myosin Va and Mlph.

The skin serves as a barrier against environmental stresses. Melanocytes synthesize melanin to protect against ultraviolet (UV) radiation; however, excessive melanin can lead to hyperpigmentation disorders. Proper pigment distribution requires melanosome transport, mediated by a complex of Mlph, Myo Va, and Rab27a. Dysregulation of this transport machinery disrupts pigment homeostasis and contributes to various pigmentation disorders. The aryl hydrocarbon receptor and transcription factor TFAP2A are known regulators of melanocyte function, but their direct regulatory relationship remains unclear. Understanding how these pathways converge is essential for elucidating the molecular basis of environmentally induced pigmentation. Here, we identify a signaling axis in which AHR activation increases TFAP2A expression, leading to the upregulation of Myo Va and Mlph. Conversely, AHR inhibition caused melanosome aggregation and reduced their expression. Mechanistically, AHR binds to the intron 1 enhancer of TFAP2A, and TFAP2A directly targets intron 1 regions of Myo Va and Mlph. Collectively, these findings reveal that the AHR-TFAP2A axis orchestrates melanosome transport in response to environmental stimuli and may represent a potential therapeutic target for environmentally induced pigmentation disorders.