Photoprotective melanin is maintained within keratinocytes in a storage lysosome

Abstract In the skin, melanin is synthesized by melanocytes within melanosomes, and transferred to keratinocytes. After being phagocytosed by keratinocytes, melanin polarizes to supranuclear caps that protect against the genotoxic effects of ultraviolet radiation. We provide evidence that melanin-containing phagosomes undergo a canonical maturation process, with the sequential acquisition of early and late endosomal markers. Subsequently, these phagosomes fuse with active lysosomes, leading to the formation of a melanin-containing phagolysosome that we named melanokerasome. Melanokerasomes achieve juxtanuclear positioning via lysosomal trafficking regulators Rab7 and RILP. Mature melanokerasomes exhibit lysosomal markers, elude connections with the endo/phagocytic pathway, are weakly degradative, retain undigested cargo and are likely tethered to the nuclear membrane. We propose that they represent a lysosomal-derived storage compartment that has exited the lysosome cycle, akin to the formation of lipofuscin in aged cells and dysfunctional lysosomes in lysosomal storage and age-related diseases. This storage lysosome allows melanin to persist for long periods, where it can exert its photoprotective effect efficiently.