RRC ID 78554
Author Waku T, Nakada S, Masuda H, Sumi H, Wada A, Hirose S, Aketa I, Kobayashi A.
Title The CNC-family transcription factor Nrf3 coordinates the melanogenesis cascade through macropinocytosis and autophagy regulation.
Journal Cell Rep
Abstract Melanin is a pigment produced from the amino acid L-tyrosine in melanosomes. The CNC-family transcription factor Nrf3 is expressed in the basal layer of the epidermis, where melanocytes reside, but its melanogenic function is unclear. Here, we show that Nrf3 regulates macropinocytosis and autophagy to coordinate melanogenesis cascade. In response to an exogenous inducer of melanin production, forskolin, Nrf3 upregulates the core melanogenic gene circuit, which includes Mitf, Tyr, Tyrp1, Pmel, and Oca2. Furthermore, Nrf3 induces the gene expression of Cln3, an autophagosome-related factor, for melanin precursor uptake by macropinocytosis. Ulk2 and Gabarapl2 are also identified as Nrf3-target autophagosome-related genes for melanosome formation. In parallel, Nrf3 prompts autolysosomal melanosome degradation for melanocyte survival. An endogenous melanogenic inducer αMSH also activates Nrf3-mediated melanin production, whereas it is suppressed by an HIV-1 protease inhibitor, nelfinavir. These findings indicate the significant role of Nrf3 in the melanogenesis and the anti-melanogenic potential of nelfinavir.
Volume 42(1)
Pages 111906
Published 2023-1-31
DOI 10.1016/j.celrep.2022.111906
PII S2211-1247(22)01805-8
PMID 36640303
MeSH Autophagy / genetics Melanins* / metabolism Melanocytes / metabolism Melanosomes / metabolism Microphthalmia-Associated Transcription Factor / genetics Microphthalmia-Associated Transcription Factor / metabolism Monophenol Monooxygenase / metabolism Nelfinavir / metabolism Transcription Factors* / metabolism Tyrosine / metabolism
Human and Animal Cells B16F10(RCB2630)