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Thioxothiazolidin derivative, 4‐OST, inhibits melanogenesis by enhancing the specific recruitment of tyrosinase‐containing vesicles to lysosome
Author(s) -
Isogawa Kenta,
Asano Masataka,
Hayazaki Masumi,
Koga Kenichi,
Watanabe Miyu,
Suzuki Keiichi,
Kobayashi Takahiro,
Kawaguchi Kyoka,
Ishizuka Akane,
Kato Shinya,
Ito Hironari,
Hamamoto Akie,
Koyama Hiroko,
Furuta Kyoji,
Takemori Hiroshi
Publication year - 2021
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.29895
Subject(s) - tyrosinase , melanosome , lysosome , chemistry , biochemistry , melanin , cathepsin l , cathepsin b , microbiology and biotechnology , enzyme , cathepsin , biology
Abstract Tyrosinase catalyzes the rate‐limiting step in melanin synthesis. Melanin is synthesized from l ‐tyrosin in the melanosomes, where tyrosinase and other melanogenic factors are recruited via the vesicle transport system. Genetic and biochemical approaches have revealed a correlation between impairments in the vesicle transport system and albinism. However, the specificity of the individual transport systems for the corresponding melanogenic factors has not been well elucidated yet. Here, we report that the thioxothiazolidin derivative, 4‐OST (4‐[(5E)‐5‐[(4‐fluorophenyl)methylidene]‐4‐oxo‐2‐sulfanylidene‐1,3‐thiazolidin‐3‐yl]‐4‐azatricyclo [5.2.1.0 2 ,6]dec‐8‐ene‐3,5‐dione: CAS RN. 477766‐87‐3) strongly inhibited melanogenesis in mouse melanoma B16F10 cells. 4‐OST reduces tyrosinase protein levels without affecting its messenger RNA levels or enzymatic activity. Although a reduction in tyrosinase protein level was observed in the presence of a protein synthesis inhibitor, the reduction may be coupled with protein synthesis. Similarly, GIF‐2202 (a derivative of 4‐OST) lowers tyrosinase protein levels without affecting the levels of another melanogenic enzyme, tyrosinase‐related protein 1 (TYRP1) level. The reduction in tyrosinase protein level is associated with an increase in the levels of the lysosomal proteinase cathepsin S. Chloroquine, a lysosome inhibitor, restored the tyrosinase protein level downregulated by GIF‐2202, although no effects of other inhibitors (against proteasome, autophagy, or exocytosis) were observed. In addition, GIF‐2202 segregated the immunofluorescence signals of tyrosinase from those of TYRP1. Chloroquine treatment resulted in co‐localization of tyrosinase and cathepsin S signals near the perinuclear region, suggesting that 4‐OST and GIF‐2202 may alter the destination of the tyrosinase vesicle from the melanosome to the lysosome. 4‐OST and GIF‐2202 can be new tools for studying the tyrosinase‐specific vesicle transport system.