FBXL家族在哺乳动物生物节律中调控作用的研究进展

doi:10.11843/j.issn.0366-6964.2020.02.002

摘要/Abstract

摘要： F-box富含亮氨酸重复蛋白3基因（F-box and leucine rich repeat protein 3，FBXL3）能编码含F-box结构域的蛋白，属于F-box蛋白家族成员，在细胞核中发挥功能。F-box富含亮氨酸重复蛋白21基因（F-box and leucine rich repeat protein 21，FBXL21）位于细胞质中，其功能与FBXL3基因功能存在拮抗作用。FBXL3与FBXL21蛋白在哺乳动物体内产生分子昼夜节律的负反馈循环中均都起重要作用。FBXL3通过形成SCF（SKP1-CUL1-F-box）复合物行使E3泛素连接酶功能，并通过泛素化促进隐花色素（Cryptochrome，CRY）蛋白的降解参与生物钟调控，FBXL21通过泛素化使CRY蛋白积累参与生物钟调控，两者对于CRY蛋白的拮抗作用能够稳定哺乳动物生物钟。本文首先介绍了生物节律以及生物钟分子的组成，然后综述了FBXL家族基因在昼夜节律循环中的调控作用及其突变后对季节性发情性状的影响，有助于后续探索FBXL家族基因突变后影响绵羊季节性发情性状的具体分子机制，为利用现代生物技术改变绵羊发情的季节性提供新思路。

关键词: 生物节律, F-box富含亮氨酸重复蛋白3基因, F-box和富含亮氨酸的重复蛋白21基因, 季节性发情, 分子机制, 绵羊

Abstract: The F-box and leucine rich repeat protein 3 (FBXL3) gene encodes the protein containing the F-box domain. It belongs to the F-box protein family and plays a role in the nucleus.The F-box and leucine rich repeat protein 21 (FBXL21) is located in the cytoplasm, and its function is antagonistic to the function of FBXL3 gene. FBXL3 and FBXL21 proteins both play important roles in the negative feedback cycle of molecular circadian rhythm in mammals. FBXL3 participates in the regulation of biological clock by forming SCF complex, which exercise E3 ubiquitin ligase function and promote the degradation of CRY protein through ubiquitination. FBXL21 makes CRY protein accumulation to participate in biological clock regulation through ubiquitination. The antagonism of FBXL3 and FBXL21 to CRY protein can stabilize the biological clock of mammals. In this review, the biological rhythm and the elements of biological clock were introduced firstly. Then, the regulation mechanism of FBXL family in circadian rhythm and the effects of FBXL family mutation on seasonal estrus traits in sheep were reviewed. It is helpful to explore the molecular mechanism of FBXL family mutation affecting sheep seasonal estrus deeply, and provide new ideas for changing sheep estrous season using modern biotechnology.

Key words: biological rhythm, FBXL3 gene, FBXL21 gene, seasonal estrus, molecular mechanism, sheep

中图分类号:

S852.2

钟英杰, 向光明, 狄冉, 胡文萍, 王翔宇, 储明星, 刘秋月. FBXL家族在哺乳动物生物节律中调控作用的研究进展[J]. 畜牧兽医学报, 2020, 51(2): 217-226.

ZHONG Yingjie, XIANG Guangming, DI Ran, HU Wenping, WANG Xiangyu, CHU Mingxing, LIU Qiuyue. Advances in the Regulation of FBXL Family in Mammalian Biorhythms[J]. Acta Veterinaria et Zootechnica Sinica, 2020, 51(2): 217-226.

参考文献 61

[1]	ZHU B K,DACSO C C,O'MALLEY B W.Unveiling "Musica Universalis" of the cell:a brief history of biological 12-hour rhythms[J].J Endocr Soc,2018,2(7):727-752.
[2]	ANGELOPOULOU E,QUIGNON C,KRIEGSFELD L J,et al.Functional implications of RFRP-3 in the central control of daily and seasonal rhythms in reproduction[J].Front Endocrinol,2019,10:183.
[3]	ROBLES M S,HUMPHREY S J,MANN M.Phosphorylation is a central mechanism for circadian control of metabolism and physiology[J].Cell Metab,2017,25(1):118-127.
[4]	BAEK M,VIRGILIO S,LAMB T M,et al.Circadian clock regulation of the glycogen synthase (gsn) gene by WCC is critical for rhythmic glycogen metabolism in Neurospora crassa[J].Proc Natl Acad Sci U S A,2019,116(21):10435-10440.
[5]	REFINETTI R.Integration of biological clocks and rhythms[J].Compr Physiol,2012,2(2):1213-1239.
[6]	LORENZ N,SPADA J,SANDER C,et al.Circadian skin temperature rhythms,circadian activity rhythms and sleep in individuals with self-reported depressive symptoms[J].J Psychiatr Res,2019,117:38-44.
[7]	POGACH M,THOMAS R J.Challenging circadian rhythm disorder cases[J].Neurol Clin,2019,37(3):579-599.
[8]	WANG D Z,HAN X,LI C,et al.FBXL3 is regulated by miRNA-4735-3p and suppresses cell proliferation and migration in non-small cell lung cancer[J].Pathol Res Pract,2019,215(2):358-365.
[9]	NORTH B J,LIU Y Y,INUZUKA H,et al.The role of FBXL subfamily of F-box proteins in tumorigenesis[M]//INUZUKA H,WEI W Y.SCF and APC E3 Ubiquitin Ligases in Tumorigenesis.Cham:Springer,2014:47-71.
[10]	SERIN Y,ACAR TEK N.Effect of circadian rhythm on metabolic processes and the regulation of energy balance[J].Ann Nutr Metab,2019,74(4):322-330.
[11]	OREM J M.Rhythms of life:the biological clocks that control the daily lives of every living thing by Russell G Foster,Leon Kreitzman[J].Quart Rev Biol,2005,80(2):266-267.
[12]	HODGES E L,ASHPOLE N M.Aging circadian rhythms and cannabinoids[J].Neurobiol Aging,2019,79:110-118.
[13]	付聪,于欢,陈云飞.昼夜节律系统与成人昼夜节律睡眠觉醒障碍[J].生理科学进展,2019,50(1):35-40.F C,YU H,CHEN Y F.Circadian rhythm and adult circadian rhythm sleep-wake disorders[J].Progress in Physiological Sciences,2019,50(1):35-40.(in Chinese)
[14]	PENG H,ZHU Y,GOLDBERG J,et al.DNA methylation of five core circadian genes jointly contributes to glucose metabolism:a gene-set analysis in monozygotic twins[J].Front Genet,2019,10:329.
[15]	马倩雯.生物节律的研究进展[J].重庆医学,2019,48(1):129-130.M Q W.Research progress of biological rhythm[J].Chongqing Medicine,2019,48(1):129-130.(in Chinese)
[16]	DALLA BENETTA E,BEUKEBOOM L W,VAN DE ZANDE L.Adaptive differences in circadian clock gene expression patterns and photoperiodic diapause induction in Nasonia vitripennis[J].Am Nat,2019,193(6):881-896.
[17]	MAYWOOD E S,CHESHAM J E,QING-JUN M,et al.Tuning the period of the mammalian circadian clock:additive and independent effects of CK1εTau and Fbxl3Afh mutations on mouse circadian behavior and molecular pacemaking[J].J Neurosci, 2011, 31(4):1539-1544.
[18]	MAYWOOD E S,REDDY A B,WONG G K Y,et al.Synchronization and maintenance of timekeeping in suprachiasmatic circadian clock cells by neuropeptidergic signaling[J].Curr Biol,2006,16(6):599-605.
[19]	LIU A C,WELSH D K,KO C H,et al.Intercellular coupling confers robustness against mutations in the SCN circadian clock network[J].Cell,2007,129(3):605-616.
[20]	BUGGE A,FENG D,EVERETT L J,et al.Rev-erbα and Rev-erbβ coordinately protect the circadian clock and normal metabolic function[J].Genes Dev,2012,26(7):657-667.
[21]	XING W M,BUSINO L,HINDS T R,et al.SCFFBXL3 ubiquitin ligase targets cryptochromes at their cofactor pocket[J].Nature, 2013,496(7443):64-68.
[22]	占思远,罗万伟,程波,等.山羊clock和cry1基因的克隆及其在大脑和垂体中表达差异的研究[J].畜牧兽医学报, 2012,43(11):1716-1722.ZAN S Y,LUO W W,CHENG B,et al.Molecular cloning and differential expression of clock and cry1 genes in goat brain and pituitary[J].Acta Veterinaria et Zootechnica Sinica,2012,43(11):1716-1722.(in Chinese)
[23]	CORREIA S P,CHAN A B,VAUGHAN M,et al.The circadian E3 ligase complex SCFFBXL3+CRY targets TLK2[J].Sci Rep,2019,9(1):198.
[24]	CHEN R,SCHIRMER A,LEE Y, et al. Rhythmic PER abundance defines a critical nodal point for negative feedback within the circadian clock mechanism[J].Mol Cell,2009,36(3):417-430.
[25]	BODEN M J, VARCOE T J, KENNAWAY D J. Circadian regulation of reproduction:from gamete to offspring[J]. Prog Biophys Mol Biol, 2013,113(3):387-397.
[26]	YUMIMOTO K,MUNEOKA T,TSUBOI T,et al.Substrate binding promotes formation of the Skp1-Cul1-Fbxl3(SCFFbxl3) protein complex[J].J Biol Chem,2013,288(45):32766-32776.
[27]	CHEN D,LIU X L,XIA T,et al.A multidimensional characterization of E3 ubiquitin ligase and substrate interaction network[J]. iScience,2019,16:177-191.
[28]	SHIROGANE T,JIN J P,ANG X L,et al.SCFβ-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1(Per1) protein[J].J Biol Chem,2005,280(29):26863-26872.
[29]	时广森.FBXL3对近日节律作用机制的研究[D].南京:南京大学,2014.SI G S.The roles of FBXL3 in regulating circadian clock[D].Nanjing:Nanjing University,2014.(in Chinese)
[30]	HUBER A L,PAPP S,CHAN A,et al.CRY2 and FBXL3 cooperatively degrade c-MYC[J].Mol Cell,2016,64(4):774-789.
[31]	BUSINO L,BASSERMANN F,MAIOLICA A,et al.SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins[J].Science,2007,316(5826):900-904.
[32]	SIEPKA S M,YOO S H,PARK J,et al. Genetics and neurobiology of circadian clocks in mammals[J].Cold Spring Harb Symp Quant Biol,2007,72:251-259.
[33]	GODINHO S I H,MAYWOOD E S,SHAW L,et al.The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period[J].Science,2007,316(5826):897-900.
[34]	MAGGI S,BALZANI E,LASSI G,et al.The after-hours circadian mutant has reduced phenotypic plasticity in behaviors at multiple timescales and in sleep homeostasis[J].Sci Rep,2017,7(1):17765.
[35]	ANSAR M,PARACHA S A,SERRETTI A,et al.Biallelic variants in FBXL3 cause intellectual disability,delayed motor development and short stature[J].Hum Mol Genet,2019,28(6):972-979.
[36]	HIRANO A,YUMIMOTO K,TSUNEMATSU R,et al.FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes[J].Cell,2013,152(5):1106-1118.
[37]	CHEN X N,WANG X,SUN C,et al.FBXL21 association with schizophrenia in Irish family and case-control samples[J].Am J Med Genet B Neuropsychiatr Genet,2008,147B(7):1231-1237.
[38]	LI Q,LI Y,WANG X,et al.Fbxl4 serves as a clock output molecule that regulates sleep through promotion of rhythmic degradation of the GABAA receptor[J].Curr Biol,2017,27(23):3616-3625.e5.
[39]	RUIZ J C,BRUICK R K.F-box and leucine-rich repeat protein 5(FBXL5):sensing intracellular iron and oxygen[J].J Inorg Biochem,2014,133:73-77.
[40]	袁曼曼.Fbxl5和Myf6基因的多态性与京海黄鸡生长、繁殖性能的关联分析及表达规律研究[D].扬州:扬州大学,2018.YAN M M.Studies on the genetic effects of Fbxl5 and Myf6 gene on growth and reproductive traits and its expression characterization in Jinghai yellow chicken[D].Yangzhou:Yangzhou University,2018.(in Chinese)
[41]	CHEN Z W,LIU B,TANG N W,et al.FBXL5-mediated degradation of single-stranded DNA-binding protein hSSB1 controls DNA damage response[J].Nucleic Acids Res,2014,42(18):11560-11569.
[42]	FUNG E,RICHTER C,YANG H B,et al.FBXL13 directs the proteolysis of CEP192 to regulate centrosome homeostasis and cell migration[J].EMBO Rep,2018,19(3):e44799.
[43]	ZHU J J,DENG S S,DUAN J,et al.FBXL20 acts as an invasion inducer and mediates E-cadherin in colorectal adenocarcinoma[J]. Oncol Lett,2014,7(6):2185-2191.
[44]	张博瀚,吴庆琛.FBXL20对人非小细胞肺癌A549细胞生长的影响[J].第三军医大学学报,2018,40(9):795-800.ZANG B H,WU Q C.Effects of FBXL20 on proliferation in human non-small cell lung cancer A549 cells[J].Journal of Third Military Medical University,2018,40(9):795-800.(in Chinese)
[45]	SIEPKA S M,YOO S H,PARK J,et al.Circadian mutant overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression[J].Cell,2007,129(5):1011-1023.
[46]	SHI G S,XING L J,LIU Z W,et al.Dual roles of FBXL3 in the mammalian circadian feedback loops are important for period determination and robustness of the clock[J].Proc Natl Acad Sci U S A,2013,110(12):4750-4755.
[47]	YOO S H,MOHAWK J A,SIEPKA S M,et al.Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm[J].Cell,2013,152(5):1091-1105.
[48]	ROSENSWEIG C,REYNOLDS K A,GAO P,et al.An evolutionary hotspot defines functional differences between CRYPTOCHROMES[J]. Nat Commun,2018,9(1):1138.
[49]	VAUGHAN M,JORDAN S D,DUGLAN D,et al.Phosphorylation of CRY1 serine 71 alters voluntary activity but not circadian rhythms in vivo[J].J Biol Rhythms,2019,34(4):401-409.
[50]	DARDENTE H,MENDOZA J,FUSTIN J M.Implication of the F-box protein FBXL21 in circadian pacemaker function in mammals[J].PLoS One,2008,3(10):e3530.
[51]	CHU M X,HE Y Q,CHENG D X,et al.Association between expression of reproductive seasonality and alleles of melatonin receptor 1A in goats[J].Anim Reprod Sci,2007,101(3-4):276-284.
[52]	孙旭,张哲,孙琛,等.褪黑素对大鼠纤维化TGF-β1/Smads信号通路干预研究[J].黑龙江农业科学,2019(1):58-61.SN X,ZHANG Z,SUN C,et al.Intervention study of melatonin on TGF-β1/Smads signaling pathway in rat fibrosis[J]. Heilongjiang Agricultural Sciences,2019(1):58-61.(in Chinese)
[53]	李华振,刘武军,刘秋月,等.甲状腺激素受体基因调控动物繁殖的研究进展[J].畜牧兽医学报,2019,50(2):243-252.L H Z,LIU W J,LIU Q Y,et al.Research progress on the regulative role of thyroid hormone receptor gene in animal reproduction[J].Acta Veterinaria et Zootechnica Sinica,2019,50(2):243-252.(in Chinese)
[54]	HUANG D W,WANG J X,LIU Q Y,et al.Analysis on DNA sequence of TSHB gene and its association with reproductive seasonality in goats[J].Mol Biol Rep,2013,40(2):1893-1904.
[55]	KOVANEN L,SAARIKOSKI S T,AROMAA A,et al.ARNTL (BMAL1) and NPAS2 gene variants contribute to fertility and seasonality[J].PLoS One,2010,5(4):e10007.
[56]	CLARKE I J,SMITH J T.The role of kisspeptin and gonadotropin inhibitory hormone (GnIH) in the seasonality of reproduction in sheep[J].Soc Reprod Fertil Suppl,2010,67:159-169.
[57]	陈健楠,王琪,王媛媛,等.CRY1在雄性牦牛生殖轴中的表达与分布[J].农业生物技术学报,2019,27(10):1869-1877.CEN J N,WANG Q,WANG Y Y,et al.Expression and distribution of CRY1 in the reproductive axis of male yak (Bos grunniens)[J].Journal of Agricultural Biotechnology,2019,27(10):1869-1877.(in Chinese)
[58]	NAVAL-SANCHEZ M,NGUYEN Q,MCWILLIAM S,et al.Sheep genome functional annotation reveals proximal regulatory elements contributed to the evolution of modern breeds[J].Nat Commun,2018,9(1):859.
[59]	POSBERGH C J,THONNEY M L,HUSON H J.Genomic approaches identify novel gene associations with out of season lambing in sheep[J].J Hered,2019,110(5):577-586.
[60]	CAO X H,WANG X Y,LU L L,et al.Expression and functional analysis of the BCL2-associated agonist of cell death (BAD) gene in the sheep ovary during the reproductive cycle[J].Front Endocrinol,2018,9:512.
[61]	WANG X N,SU X X,CHENG S Q,et al.MYC modulators in cancer:a patent review[J].Expert Opin Ther Pat,2019, 29(5):353-367.