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J. Biol. Chem., Vol. 279, Issue 15, 15427-15433, April 9, 2004

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Fatty Acids Regulate Pigmentation via Proteasomal Degradation of Tyrosinase

A NEW ASPECT OF UBIQUITIN-PROTEASOME FUNCTION^*

Hideya Ando, Hidenori Watabe, Julio C. Valencia, Ken-ichi Yasumoto, Minao Furumura, Yoko Funasaka, Masahiro Oka, Masamitsu Ichihashi, and Vincent J. Hearing¶

From the Laboratory of Cell Biology, NCI, National Institutes of Health, Bethesda, Maryland 20892 and the Department of Dermatology, Kobe University School of Medicine, Kobe 650-0017, Japan

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.

Received for publication, December 15, 2003

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Laboratory of Cell Biology, Bldg. 37, Rm. 1B25, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-1564; Fax: 301-402-8787; E-mail: hearingv{at}nih.gov.

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