title: Fatty acids regulate pigmentation via proteasomal degradation of tyrosinase: a new aspect of ubiquitin-proteasome function.
abstract: Fatty acids are common components of biological membranes that are known to play important roles in intracellular signaling. We report here a novel mechanism by which fatty acids regulate the degradation of tyrosinase, a critical enzyme associated with melanin biosynthesis in melanocytes and melanoma cells. Linoleic acid (unsaturated fatty acid, C18:2) accelerated the spontaneous degradation of tyrosinase, whereas palmitic acid (saturated fatty acid, C16:0) retarded the proteolysis. The linoleic acid-induced acceleration of tyrosinase degradation could be abrogated by inhibitors of proteasomes, the multicatalytic proteinase complexes that selectively degrade intracellular ubiquitinated proteins. Linoleic acid increased the ubiquitination of many cellular proteins, whereas palmitic acid decreased such ubiquitination, as compared with untreated controls, when a proteasome inhibitor was used to stabilize ubiquitinated proteins. Immunoprecipitation analysis also revealed that treatment with fatty acids modulated the ubiquitination of tyrosinase, i.e. linoleic acid increased the amount of ubiquitinated tyrosinase whereas, in contrast, palmitic acid decreased it. Furthermore, confocal immunomicroscopy showed that the colocalization of ubiquitin and tyrosinase was facilitated by linoleic acid and diminished by palmitic acid. Taken together, these data support the view that fatty acids regulate the ubiquitination of tyrosinase and are responsible for modulating the proteasomal degradation of tyrosinase. In broader terms, the function of the ubiquitin-proteasome pathway might be regulated physiologically, at least in part, by fatty acids within cellular membranes.
authors.affiliation: Laboratory of Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA. hearingv@nih.gov
authors.forename: Hideya
authors.initials: H
authors.lastname: Ando
authors.forename: Hidenori
authors.initials: H
authors.lastname: Watabe
authors.forename: Julio C
authors.initials: JC
authors.lastname: Valencia
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Yasumoto
authors.forename: Minao
authors.initials: M
authors.lastname: Furumura
authors.forename: Yoko
authors.initials: Y
authors.lastname: Funasaka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Oka
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Ichihashi
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Hearing
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D007700:Kinetics; D019787:Linoleic Acid / Q000494:pharmacology; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D014442:Monophenol Monooxygenase / Q000737:chemistry* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry*; D019308:Palmitic Acid / Q000378:metabolism; D010858:Pigmentation; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D009097:Multienzyme Complexes; D011500:Protein Synthesis Inhibitors; D025801:Ubiquitin; D019308:Palmitic Acid; D003513:Cycloheximide; D019787:Linoleic Acid; D014442:Monophenol Monooxygenase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex