改变黑素小体腔内pH值影响表皮黑素细胞的黑素生成
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摘要
黑素小体是一种真核生物细胞中高度特化的用于合成与贮存黑素的细胞器。它最早起源于溶酶体衍生小囊泡,为单层质膜包裹的近似封闭的酸性细胞器,其腔内环境的pH值大约是4～5。位于黑素小体膜上的酪氨酸酶,被认为是黑素合成的主要限速酶,它的最适pH值为6.8,这就意味着在酸性黑素小体内酪氨酸酶处于未活化状态。有研究表明,黑素小体膜上存在有多种不同类型的离子通道和质子泵,协同参与调节和维持着黑素小体腔内的偏酸环境。改变黑素小体腔内pH值可直接影响黑素细胞的黑素合成,为临床治疗色素异常相关疾病以及皮肤美白产品的研发提供了一个新途径。
The melanosome is a highly specialized organelle in eukaryotic cells,which serves as the site for synthesis and storage of melanin. Melanosomes are originated from lysosomal vesicles and encapsulated by monolayer plasma membrane to form acidic and almost closed compartments,in which pH is approximately 4～5. Tyrosinase,a key rate-limiting enzyme in the melanin synthesis,is localized to the membrane of melanosomes and its optimal pH is 6.8,that means this membrane-bound enzyme is largely inactive in the acidic melanosomes. It is well established that there are many ion channels and transporters in the melanosomal membrane to regulate or maintain this slightly acidic intraluminal pH. Change of the melanogenesis in epidermal melanocytes through controlling the intramelanosomal pH paves a way for treatment of pigmentary disorders and for development of skin-lightening cosmetic products.
The melanosome is a highly specialized organelle in eukaryotic cells,which serves as the site for synthesis and storage of melanin. Melanosomes are originated from lysosomal vesicles and encapsulated by monolayer plasma membrane to form acidic and almost closed compartments,in which pH is approximately 4～5. Tyrosinase,a key rate-limiting enzyme in the melanin synthesis,is localized to the membrane of melanosomes and its optimal pH is 6.8,that means this membrane-bound enzyme is largely inactive in the acidic melanosomes. It is well established that there are many ion channels and transporters in the melanosomal membrane to regulate or maintain this slightly acidic intraluminal pH. Change of the melanogenesis in epidermal melanocytes through controlling the intramelanosomal pH paves a way for treatment of pigmentary disorders and for development of skin-lightening cosmetic products.
引文
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[14] Watabe H,Valencia JC,Yasumoto K,et al.Regulation of tyrosinase processing and trafficking by organellar pH and by proteasome activity [J].J Biol Chem,2004,279(9):7971-7981.
[15] Aquaron R,Soufir N,Bergé-Lefranc JL,et al.Oculocutaneous albinism type 2 (OCA2) with homozygous 2.7-kb deletion of the P gene and sickle cell disease in a Cameroonian family.Identification of a common TAG haplotype in the mutated P gene [J].J Hum Genet,2007,52(9):771-780.
[16] Chen K,Manga P,Orlow SJ.Pink-eyed dilution protein controls the processing of tyrosinase [J].Mol Biol Cell,2002,13(6):1953-1964.
[17] Puri N,Gardner JM,Brilliant MH.Aberrant pH of melanosomes in pink-eyed dilution (p) mutant melanocytes [J].J Invest Dermatol,2000,115(4):607-613.
[18] Calcraft PJ,Ruas M,Pan Z,et al.NAADP mobilizes calcium from acidic organelles through two-pore channels [J].Nature,2009,459(7246):596-600.
[19] Morgan AJ,Galione A.NAADP induces pH changes in the lumen of acidic Ca2+ stores [J].Biochem J,2007,402(2):301-310.
[20] Bellono NW,Escobar IE,Oancea E.A melanosomal two-pore sodium channel regulates pigmentation [J].Sci Rep,2016,6:26570.
[21] Ambrosio AL,Boyle JA,Aradi AE,et al.TPC2 controls pigmentation by regulating melanosome pH and size [J].Proc Natl Acad Sci USA,2016,113(20):5622-5627.
[22] Pilon-Thomas S,Kodumudi KN,EI-Kenawi AE,et al.Neutralization of tumor acidity improves antitumor responses to immunotherapy [J].Cancer Res,2016,76(6):1381-1390.
[23] Yoshizaki N,Hashizume R,Masaki H.A polymethoxyflavone mixture extracted from orange peels,mainly containing nobiletin,3,3′,4′,5,6,7,8-heptamethoxyflavone and tangeretin,suppresses melanogenesis through the acidification of cell organelles,including melanosomes [J].J Dermatol Sci,2017,88(1):78-84.
[2] Chen K,Minwalla L,Ni L,et al.Correction of defective early tyrosinase processing by bafilomycin A1 and monensin in pink-eyed dilution melanocytes [J].Pigment Cell Res,2004,17(1):36-42.
[3] Hunt G,Kyne S,Ito S,et al.Eumelanin and phaeomelanin contents of human epidermis and cultured melanocytes [J].Pigment Cell Res,1995,8(4):202-208.
[4] Ancans J,Tobin DJ,Hoogduijn MJ,et al.Melanosomal pH controls rate of melanogenesis,eumelanin/phaeomelanin ratio and melanosome maturation in melanocytes and melanoma cells [J].Exp Cell Res,2001,268(1):26-35.
[5] Fuller BB,Spaulding DT,Smith DR.Regulation of the catalytic activity of preexisting tyrosinase in black and caucasian human melanocyte cell cultures [J].Exp Cell Res,2001,262(2):197-208.
[6] Maxson ME,Grinstein S.The vacuolar-type H-ATPase at a glance-more than a proton pump [J].J Cell Sci,2014,127(Pt23):4987-4993.
[7] Benlekbir S,Bueler SA,Rubinstein JL.Structure of the vacuolar-type ATPase from Saccharomyces cerevisiae at 11-? resolution [J].Nat Struct Mol Biol,2012,19(12):1356-1362.
[8] Muench SP,Huss M,Song CF,et al.Cryo-electron microscopy of the vacuolar ATPase motor reveals its mechanical and regulatory complexity [J].J Mol Biol,2009,386(4):989-999.
[9] Basrur V,Yang F,Kushimoto T,et al.Proteomic analysis of early melanosomes:identification of novel melanosomal proteins [J].J Proteome Res,2003,2(1):69-79.
[10] Ancans J,Hoogduijn MJ,Thody AJ.Melanosomal pH,pink locus protein and their roles in melanogenesis [J].J Invest Dermatol,2001,117(1):158-159.
[11] Lamason RL,Mohideen MA,Mest JR,et al.SLC24A5,a putative cation exchanger,affects pigmentation in zebrafish and humans [J].Science,2005,310(5755):1782-1786.
[12] Bin BH,Bhin J,Yang SH,et al.Membrane-associated transporter protein (MATP) regulates melanosomal pH and influences tyrosinase activity [J].PLoS One,2015,10(6):e0129273.
[13] Smith DR,Spaulding DT,Glenn HM,et al.The relationship between Na(+)/H(+) exchanger expression and tyrosinase activity in human melanocytes [J].Exp Cell Res,2004,298(2):521-534.
[14] Watabe H,Valencia JC,Yasumoto K,et al.Regulation of tyrosinase processing and trafficking by organellar pH and by proteasome activity [J].J Biol Chem,2004,279(9):7971-7981.
[15] Aquaron R,Soufir N,Bergé-Lefranc JL,et al.Oculocutaneous albinism type 2 (OCA2) with homozygous 2.7-kb deletion of the P gene and sickle cell disease in a Cameroonian family.Identification of a common TAG haplotype in the mutated P gene [J].J Hum Genet,2007,52(9):771-780.
[16] Chen K,Manga P,Orlow SJ.Pink-eyed dilution protein controls the processing of tyrosinase [J].Mol Biol Cell,2002,13(6):1953-1964.
[17] Puri N,Gardner JM,Brilliant MH.Aberrant pH of melanosomes in pink-eyed dilution (p) mutant melanocytes [J].J Invest Dermatol,2000,115(4):607-613.
[18] Calcraft PJ,Ruas M,Pan Z,et al.NAADP mobilizes calcium from acidic organelles through two-pore channels [J].Nature,2009,459(7246):596-600.
[19] Morgan AJ,Galione A.NAADP induces pH changes in the lumen of acidic Ca2+ stores [J].Biochem J,2007,402(2):301-310.
[20] Bellono NW,Escobar IE,Oancea E.A melanosomal two-pore sodium channel regulates pigmentation [J].Sci Rep,2016,6:26570.
[21] Ambrosio AL,Boyle JA,Aradi AE,et al.TPC2 controls pigmentation by regulating melanosome pH and size [J].Proc Natl Acad Sci USA,2016,113(20):5622-5627.
[22] Pilon-Thomas S,Kodumudi KN,EI-Kenawi AE,et al.Neutralization of tumor acidity improves antitumor responses to immunotherapy [J].Cancer Res,2016,76(6):1381-1390.
[23] Yoshizaki N,Hashizume R,Masaki H.A polymethoxyflavone mixture extracted from orange peels,mainly containing nobiletin,3,3′,4′,5,6,7,8-heptamethoxyflavone and tangeretin,suppresses melanogenesis through the acidification of cell organelles,including melanosomes [J].J Dermatol Sci,2017,88(1):78-84.