NNT mediates redox-dependent pigmentation via a UVB- and MITF-independent mechanism

被引：51

作者：

Allouche, Jennifer ^{[1
]}

Rachmin, Inbal ^{[1
]}

Adhikari, Kaustubh ^{[2
,3
,4
]}

Pardo, Luba M. ^{[5
]}

Lee, Ju Hee ^{[6
,7
]}

McConnell, Alicia M. ^{[8
,9
,10
]}

Kato, Shinichiro ^{[1
,46
]}

Fan, Shaohua ^{[11
]}

Kawakami, Akinori ^{[1
]}

Suita, Yusuke ^{[1
]}

Wakamatsu, Kazumasa ^{[12
]}

Igras, Vivien ^{[1
]}

Zhang, Jianming ^{[13
]}

Navarro, Paula P. ^{[14
,15
]}

Lugo, Camila Makhlouta ^{[14
,15
]}

Noonan, Haley R. ^{[8
,9
,10
]}

Christie, Kathleen A. ^{[16
,17
,18
]}

Itin, Kaspar ^{[19
]}

Mujahid, Nisma ^{[1
,20
,21
]}

Lo, Jennifer A. ^{[1
]}

Won, Chong Hyun ^{[22
]}

Evans, Conor L. ^{[23
]}

Weng, Qing Yu ^{[1
]}

Wang, Hequn ^{[23
]}

Osseiran, Sam ^{[23
]}

Lovas, Alyssa ^{[23
]}

Nemeth, Istvan ^{[24
]}

Cozzio, Antonio ^{[25
]}

Navarini, Alexander A. ^{[19
]}

Hsiao, Jennifer J. ^{[1
]}

Nguyen, Nhu ^{[1
]}

Kemeny, Lajos, V ^{[1
,26
]}

Iliopoulos, Othon ^{[27
]}

Berking, Carola ^{[28
]}

Ruzicka, Thomas ^{[29
]}

Gonzalez-Jose, Rolando ^{[30
]}

Bortolini, Maria-Catira ^{[31
]}

Canizales-Quinteros, Samuel ^{[32
,33
]}

Acuna-Alonso, Victor ^{[34
]}

Gallo, Carla ^{[35
]}

Poletti, Giovanni ^{[35
]}

Bedoya, Gabriel ^{[36
]}

Rothhammer, Francisco ^{[37
,38
]}

Ito, Shosuke ^{[12
]}

Schiaffino, Maria Vittoria ^{[39
]}

Chao, Luke H. ^{[14
,15
]}

Kleinstiver, Benjamin P. ^{[16
,17
,18
]}

Tishkoff, Sarah ^{[40
,41
]}

Zon, Leonard, I ^{[8
,9
,10
]}

Nijsten, Tamar ^{[5
]}

机构：

[1] Harvard Med Sch, Cutaneous Biol Res Ctr, Massachusetts Gen Hosp, Dept Dermatol, Charlestown, MA 02129 USA

[2] Open Univ, Sch Math & Stat, Milton Keynes MK7 6AA, Bucks, England

[3] UCL, Dept Genet Evolut & Environm, London WC1E 6BT, England

[4] UCL, UCL Genet Inst, London WC1E 6BT, England

[5] Erasmus MC, Dept Dermatol, NL-3015 Rotterdam, Netherlands

[6] Yonsei Univ, Dept Dermatol, Coll Med, Seoul 03722, South Korea

[7] Yonsei Univ, Cutaneous Biol Res Inst, Coll Med, Seoul 03722, South Korea

[8] Boston Childrens Hosp, Stem Cell Program, Boston, MA 02115 USA

[9] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA

[10] Howard Hughes Med Inst, Boston, MA 02115 USA

[11] Fudan Univ, Sch Life Sci, Human Phenome Inst, State Key Lab Genet Engn, Shanghai 200438, Peoples R China

[12] Fujita Hlth Univ, Inst Melanin Chem, Toyoake, Aichi 4701192, Japan

[13] Shanghai Jiao Tong Univ, Ruijin Hosp, Natl Res Ctr Translat Med Shanghai, State Key Lab Med Genom,Sch Med, Shanghai 200025, Peoples R China

[14] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA

[15] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[16] Massachusetts Gen Hosp, Ctr Genom Med, Boston, MA 02114 USA

[17] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[18] Harvard Med Sch, Dept Pathol, Boston, MA 02115 USA

[19] Univ Hosp Basel, Dept Dermatol, CH-4031 Basel, Switzerland

[20] Boston Univ, Sch Med, Boston, MA 02118 USA

[21] Univ Utah, Dept Dermatol, Salt Lake City, UT 84132 USA

[22] Ulsan Univ, Asan Med Ctr, Dept Dermatol, Coll Med, Seoul 05505, South Korea

[23] Harvard Med Sch, Wellman Ctr Photomed, Massachusetts Gen Hosp, Charlestown, MA 02129 USA

[24] Univ Szeged, Dept Dermatol & Allergol, H-6720 Szeged, Hungary

[25] Kantonsspital St Gallen, Dept Dermatol Venerol & Allergol, CH-9007 St Gallen, Switzerland

[26] Semmelweis Univ, Dept Dermatol Venereol & Dermatooncol, H-1085 Budapest, Hungary

[27] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Boston, MA 02114 USA

[28] Friedrich Alexander Univ Erlangen Nurnberg, Univ Klinikum Erlangen, Dept Dermatol, D-91054 Erlangen, Germany

[29] Ludwig Maximilians Univ Munchen, Univ Hosp Munich, Dept Dermatol & Allergy, D-80337 Munich, Germany

[30] Consejo Nacl Invest Cient & Tecn, Ctr Nacl Patagon, Inst Patagon Ciencias Sociales & Humanas, U912OACD, Puerto Madryn, Argentina

[31] Univ Fed Rio Grande do Sul, Dept Genet, BR-91501970 Porto Alegre, RS, Brazil

[32] Univ Nacl Autonoma Mexico, Fac Quim, Unidad Genom Poblac Aplicada Salud, Mexico City 04510, DF, Mexico

[33] Inst Nacl Med Genom, Mexico City 04510, DF, Mexico

[34] Natl Inst Anthropol & Hist, Mexico City 4510, DF, Mexico

[35] Univ Peruana Cayetano Heredia, Fac Ciencias & Filosofia, Labs Invest & Desarrollo, Lima 15102, Peru

[36] Univ Antioquia, Genet Mol GENMOL, Medellin 5001000, Colombia

[37] Univ Tarapaca, Inst Alta Invest, Arica 1000009, Chile

[38] Univ Chile, Fac Med, ICBM, Programa Genet Humana, Santiago 1027, Chile

[39] IRCCS San Raffaele Sci Inst, Diabet & Endocrinol Unit, Internal Med, I-20132 Milan, Italy

[40] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA

[41] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA

[42] Fudan Univ, Key Lab Contemporary Anthropol, Minist Educ, Shanghai 200433, Peoples R China

[43] Fudan Univ, Collaborat Innovat Ctr Genet & Dev, Sch Life Sci, Shanghai 200433, Peoples R China

[44] Fudan Univ, Human Phenome Inst, Shanghai 200433, Peoples R China

[45] Aix Marseille Univ, CNRS EFS ADES, UMR 7268, F-13005 Marseille, France

[46] Nagoya Univ, Ctr 5D Cell Dynam, Dept Immunol, Grad Sch Med, Nagoya, Aichi 4668550, Japan

来源：

CELL | 2021年 / 184卷 / 16期

基金：

美国国家卫生研究院; 英国生物技术与生命科学研究理事会; 瑞士国家科学基金会; 中国国家自然科学基金;

关键词：

NICOTINAMIDE NUCLEOTIDE TRANSHYDROGENASE; MICROPHTHALMIA TRANSCRIPTION FACTOR; SKIN PIGMENTATION; PROTEASOMAL DEGRADATION; CHEMICAL-ANALYSIS; MITOFUSIN; MELANOMA; DNA; MELANOCYTES; AUTOPHAGY;

D O I：

10.1016/j.cell.2021.06.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Ultraviolet (UV) light and incompletely understood genetic and epigenetic variations determine skin color. Here we describe an UV- and microphthalmia-associated transcription factor (MITF)-independent mechanism of skin pigmentation. Targeting the mitochondrial redox-regulating enzyme nicotinamide nucleotide transhydrogenase (NNT) resulted in cellular redox changes that affect tyrosinase degradation. These changes regulate melanosome maturation and, consequently, eumelanin levels and pigmentation. Topical application of small-molecule inhibitors yielded skin darkening in human skin, and mice with decreased NNT function displayed increased pigmentation. Additionally, genetic modification of NNT in zebrafish alters melanocytic pigmentation. Analysis of four diverse human cohorts revealed significant associations of skin color, tanning, and sun protection use with various single-nucleotide polymorphisms within NNT. NNT levels were independent of UVB irradiation and redox modulation. Individuals with postinflammatory hyperpigmentation or lentigines displayed decreased skin NNT levels, suggesting an NNT-driven, redox-dependent pigmentation mechanism that can be targeted with NNT-modifying topical drugs for medical and cosmetic purposes.

引用

页码：4268 / +

页数：36

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