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Proc Natl Acad Sci U S A. 2018 Aug 14;115(33):E7728-E7737. doi: 10.1073/pnas.1803303115. Epub 2018 Jul 30.

Central role of autophagic UVRAG in melanogenesis and the suntan response.

Author information

1
Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033.
2
Institute of Chinese Medical Sciences, University of Macau, Macao, China.
3
Department of Biology, South University of Science and Technology, 518055 Shenzhen, China.
4
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, 400044 Chongqing, China.
5
Division of Infectious Diseases, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027.
6
Brain Science Center at the Institute of Basic Medical Sciences, Haidian District, 100850 Beijing, China.
7
Department of Biotechnology and Bioinformatics, College of Science and Technology, Korea University, 30019 Sejong, Republic of Korea.
8
Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033; chengyu.liang@med.usc.edu.

Abstract

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.

KEYWORDS:

BLOC-1; BRAF; MITF; UVRAG; melanosome

PMID:
30061422
PMCID:
PMC6099899
DOI:
10.1073/pnas.1803303115
[Indexed for MEDLINE]
Free PMC Article

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