Central role of autophagic UVRAG in melanogenesis and the suntan response

UV-induced cell pigmentation represents an important mechanism against skin cancers. Sun-exposed skin secretes α-MSH, which induces the lineage-specific transcriptional factor MITF and activates melanogenesis in melanocytes. Here, we show that the autophagic tumor suppressor UVRAG plays an integral...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2018-08, Vol.115 (33), p.E7728-E7737
Main Authors: Yang, Yongfei, Jang, Gyu-beom, Yang, Xuanjun, Wang, Qiaoxiu, He, Shanshan, Li, Shun, Quach, Christine, Zhao, Shihui, Li, Fan, Yuan, Zengqiang, Lee, Hye-Ra, Zhong, Hanbing, Liang, Chengyu
Format: Article
Language:English
Subjects:
Animals
Autophagy
Biological Sciences
Biosynthesis
HEK293 Cells
Humans
Melanins - biosynthesis
Melanins - genetics
Melanocytes
Melanoma
Melanoma - genetics
Melanoma - metabolism
Melanosomes
Melanosomes - genetics
Melanosomes - metabolism
Microphthalmia-associated transcription factor
Microphthalmia-Associated Transcription Factor - genetics
Microphthalmia-Associated Transcription Factor - metabolism
Organelles
Pigmentation
Pigments
PNAS Plus
Proto-Oncogene Proteins B-raf - genetics
Proto-Oncogene Proteins B-raf - metabolism
Skin cancer
Skin Pigmentation - radiation effects
Tumor suppressor genes
Tumor Suppressor Proteins - genetics
Tumor Suppressor Proteins - metabolism
Ultraviolet radiation
Ultraviolet Rays
Zebrafish
Zebrafish - genetics
Zebrafish - metabolism
Zebrafish Proteins - genetics
Zebrafish Proteins - metabolism
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Summary:UV-induced cell pigmentation represents an important mechanism against skin cancers. Sun-exposed skin secretes α-MSH, which induces the lineage-specific transcriptional factor MITF and activates melanogenesis in melanocytes. Here, we show that the autophagic tumor suppressor UVRAG plays an integral role in melanogenesis by interaction with the biogenesis of lysosome-related organelles complex 1 (BLOC-1). This interaction is required for BLOC-1 stability and for BLOC-1–mediated cargo sorting and delivery to melanosomes. Absence of UVRAG dispersed BLOC-1 distribution and activity, resulting in impaired melanogenesis in vitro and defective melanocyte development in zebrafish in vivo. Furthermore, our results establish UVRAG as an important effector for melanocytes’ response to α-MSH signaling as a direct target of MITF and reveal the molecular basis underlying the association between oncogenic BRAF and compromised UV protection in melanoma.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1803303115