25-hydroxycholesterol acts in the Golgi compartment to induce degradation of tyrosinase.
Oxysterols play a significant role in cholesterol homeostasis. 25-Hydroxycholesterol (25HC) in particular has been demonstrated to regulate cholesterol homeostasis via oxysterol-binding protein and oxysterol-related proteins, the sterol regulatory element binding protein, and the rate-limiting enzyme of cholesterol biosynthesis, hydroxymethylglutaryl coenzyme A reductase. We have examined the effect of 25HC on pigmentation of cultured murine melanocytes and demonstrated a decrease in pigmentation with an IC(50) of 0.34 microM and a significant diminution in levels of melanogenic protein tyrosinase. Pulse-chase studies of 25HC-treated cells demonstrated enhanced degradation of tyrosinase, the rate-limiting enzyme of melanin synthesis, following endoplasmic reticulum (ER) and Golgi maturation. Protein levels of GS28, a member of an ER/cis-Golgi SNARE protein complex, were also diminished in 25HC-treated melanocytes, however levels of the ER chaperone calnexin and the cis-Golgi matrix protein GM130 were unaffected. Effects of 25HC on tyrosinase were completely reversed by 4 alpha-allylcholestan-3 alpha-ol, a sterol identified by its ability to reverse effects of 25HC on cholesterol homeostasis. Finally, the addition of 25HC to lipid deficient serum inhibited correct processing of tyrosinase. We conclude that 25HC acts in the Golgi compartment to regulate pigmentation by a mechanism shared with cholesterol homeostasis.
Hall
Andrea M
AM
The Ronald O. Perelman Department of Dermatology and the Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
Krishnamoorthy
Lalitha
L
Orlow
Seth J
SJ
D000818:Animals; D002460:Cell Line; D002777:Cholestanols / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006056:Golgi Apparatus / Q000737:chemistry / Q000201:enzymology*; D006888:Hydroxycholesterols / Q000737:chemistry / Q000494:pharmacology*; D008543:Melanins / Q000037:antagonists & inhibitors; D008544:Melanocytes / Q000737:chemistry / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D050766:Qb-SNARE Proteins; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D044764:Ubiquitin-Activating Enzymes / Q000502:physiology
D002777:Cholestanols; C490971:Gosr1 protein, mouse; D006888:Hydroxycholesterols; C107473:LY 295427; D008543:Melanins; D008565:Membrane Proteins; D050766:Qb-SNARE Proteins; C007997:25-hydroxycholesterol; D002784:Cholesterol; D014442:Monophenol Monooxygenase; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D044764:Ubiquitin-Activating Enzymes