Inulavosin, a melanogenesis inhibitor, leads to mistargeting of tyrosinase to lysosomes and accelerates its degradation.

Abstract

The melanosome is a highly specialized organelle where melanin is synthesized. Tyrosinase and tyrosinase-related protein-1 (Tyrp1) are major melanosomal membrane proteins and key enzymes for melanin synthesis in melanocytes. Inulavosin, a melanogenesis inhibitor isolated from Inula nervosa (Compositae), reduced the melanin content without affecting either the enzymatic activities or the transcription of tyrosinase or Tyrp1 in B16 melanoma cells. To our knowledge, this inhibitor is previously unreported. Electron-microscopic analyses revealed that inulavosin impaired late-stage development of melanosomes (stages III and IV), in which melanin is heavily deposited. However, it did not alter the early stages of melanosomes (stages I and II), when filamentous structure is observed. Immunofluorescence analyses showed that tyrosinase, but not Tyrp1, was specifically eliminated from melanosomes in cells treated with inulavosin. Unexpectedly, inulavosin specifically accelerated the degradation of tyrosinase but not other melanosomal/lysosomal membrane proteins (Tyrp1, Pmel17, and LGP85). The degradation of tyrosinase induced by inulavosin associated with lysosomes but not the proteasome. Interestingly, lysosomal protease inhibitors restored the melanogenesis but not the targeting of tyrosinase to melanosomes in the cells treated with inulavosin. Instead, colocalization of tyrosinase with lysosome-associated membrane protein-1 at late endosomes/multivesicular bodies and lysosomes was accentuated. Taken together, inulavosin inhibits melanogenesis as a result of mistargeting of tyrosinase to lysosomes.

• Authors: Hideaki Fujita, Tomonori Motokawa, Takayuki Katagiri, Sadaki Yokota, Akitsugu Yamamoto, Masaru Himeno, Yoshitaka Tanaka
• Journal: The Journal of investigative dermatology (J Invest Dermatol) Vol. 129 Issue 6 Pg. 1489-99 (Jun 2009) ISSN: 1523-1747 [Electronic] United States
• PMID: 19110539 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2'-hydroxy-2,4,4,7,4'-pentamethylflavan
• Flavonoids
• Melanins
• Plant Extracts
• Monophenol Monooxygenase

Topics

• Animals
• Asteraceae (metabolism)
• Flavonoids (pharmacology)
• Lysosomes (metabolism)
• Melanins (metabolism)
• Melanoma, Experimental
• Melanosomes (drug effects, metabolism, ultrastructure)
• Mice
• Microscopy, Electron
• Microscopy, Fluorescence
• Microscopy, Immunoelectron
• Models, Biological
• Monophenol Monooxygenase (metabolism)
• Pigmentation
• Plant Extracts (pharmacology)
• Time Factors