Reprogramming of endolysosomes for melanogenesis in BLOC-1-deficient melanocytes

Photoprotective melanins in the skin are synthesized by epidermal melanocytes within specialized lysosome-related organelles called melanosomes. Melanosomes coexist with lysosomes; thus, melanocytes employ trafficking machineries that possess cell-type-specific functions to ensure correct cargo delivery to either the endolysosomal system or maturing melanosomes. Mutations in some of the protein complexes required for melanogenic cargo delivery, such as biogenesis of lysosome-related organelles complex 1 (BLOC-1), result in hypopigmentation due to mistrafficking of cargo to endolysosomes. We show that hypopigmented BLOC-1-deficient melanocytes retain melanogenic capacity that can be enhanced by treatment with cyclic adenosine monophosphate (cAMP)-elevating agents despite the mislocalization of melanogenic proteins. The melanin formed in BLOC-1-deficient melanocytes is not generated in melanosomes but rather within late endosomes/lysosomes to which some cargoes mislocalize. Although these organelles generally are acidic, a cohort of late endosomes/lysosomes have a sufficiently neutral pH to facilitate melanogenesis, perhaps due to mislocalized melanosomal transporters and melanogenic enzymes. Modulation of the pH of late endosomes/lysosomes by genetic manipulation or via treatment with lysosomotropic agents significantly enhances the melanin content of BLOC-1-deficient melanocytes. Our data suggest that upregulated expression of mistargeted cargoes leads to both increased tyrosinase expression and subsequent activity due to pH modulation facilitating the reprogramming of a subset of endolysosomes to replicate some functions of lysosome-related organelles.