Central role of autophagic UVRAG in melanogenesis and the suntan response

Significance Skin pigmentation provides first-line protection against UV radiation (UVR) that increases the risk of skin cancers. However, mechanisms underlying this process remain poorly understood. Here, we identified the autophagic tumor suppressor UVRAG as a bona fide player in melanosome biogenesis by targeting biogenesis of lysosome-related organelles complex 1 (BLOC-1) independently of autophagy. UVRAG maintains the localization and stability of BLOC-1 to facilitate the sorting/delivery of melanogenic cargoes. Reduced levels of UVRAG rendered cells unresponsive to UVR–α-MSH–MITF signaling and defective melanocyte development in vivo. Moreover, UVRAG-mediated melanogenesis and tanning response were impaired in oncogene-driven melanoma. This study represents a description of a noncanonical role of autophagy factor in melanogenic remodeling and also provides mechanistic insights into UVRAG in pigmentation disorder and UV-associated cancer.