WEI Chaoliang,XIA Ming,and GU Mingyao.RBFox family proteins in function and disease regulation[J].Journal of Shenzhen University Science and Engineering,2020,37(5):514-520.[doi:10.3724/SP.J.1249.2020.05514]





RBFox family proteins in function and disease regulation
WEI Chaoliang XIA Ming and GU Mingyao
Guangdong Key Laboratory of Genomic Stability and Disease Control, School of Basic Medicine Science, Health Science Center, Shenzhen University, Shenzhen 518060, Guangdong Province, P.R.China
molecular biology RNA binding protein RBFox RNA recognition motif multifunctional protein disease regulation
RNA结合蛋白(RNA binding proteins, RBPs)是细胞内一类能与单链或双链核糖核酸(ribonuleic acid, RNA)结合并形成核糖核蛋白复合体的一类蛋白.RBFox(RNA binding proteins feminine gene on X chromosome)蛋白是RNA结合蛋白家族中的重要成员,在多种动物体内的特定组织细胞中表达并发挥生物学功能.已发现的RBFox蛋白包括RBFox1、RBFox2和RBFox3,均含有进化上高度保守的RNA识别结构基序(RNA recognition motif, RRM),能特异性地与(U)GCAUG序列结合并发挥作用.目前研究揭示了RBFox蛋白是一类多功能蛋白,除了调控RNA加工过程中的经典功能可变剪接之外,还广泛参与基因转录、mRNA稳定性调节、miRNA代谢以及蛋白翻译等过程,在心脏疾病、神经系统疾病、糖尿病和癌症等疾病的发生发展过程中起重要调控作用.本文概述了目前RBFox家族在调节剪接、转录、miRNA代谢和mRNA稳定性的4个功能及其在心脏疾病、神经系统疾病、糖尿病和癌症等多种疾病方面的研究进展,为RBFox蛋白的作用机制及其对疾病调控的进一步研究提供借鉴.
RNA binding proteins (RBPs) are a class of intracellular proteins that bind to single-stranded or double-stranded RNA and form a ribonucleoprotein complex. RBFox (RNA binding proteins feminine gene on X chromosome) proteins are important members of the RNA-binding protein family and are expressed in specific tissue and cells of various animals, where they play important biological functions. Three members of the RBFox proteins, which are RBFox1, RBFox2 and RBFox3, have been discovered, and all of them contain an evolutionarily highly conserved RNA recognition motif (RRM), which specifically binds to the (U)GCAUG sequence. Current studies reveal that RBFox proteins are a kind of multifunctional proteins. In addition to regulating the classical functions of alternative splicing in RNA processing, they are also widely involved in transcription, mRNA stability, miRNA metabolism and translation processes. The RBFox proteins play pathological roles in the onset and development of many diseases including heart disease, neurological diseases, diabetes and cancer. This article gives the regulatory functions of RBFox family in splicing, transcription, miRNA metabolism and mRNA stability, and its related research progresses in heart disease, neurological disease, diabetes, cancer and other diseases. It provides a reference for further study on mechanism and disease regulation of RBFox proteins.


[1] QUINONES-VALDEZ G, TRAN S S, JUN H I, et al. Regulation of RNA editing by RNA-binding proteins in human cells[J]. Communications Biology, 2019, 2: 19.
[2] NEELAMRAJU Y, GONZALEZ-PEREZ A, BHAT-NAKSHATRI P, et al. Mutational landscape of RNA-binding proteins in human cancers[J]. RNA Biology, 2017, 15(1): 115-129.
[3] CONBOY J G. Developmental regulation of RNA processing by Rbfox proteins[J]. Wiley Interdiscip Reviews RNA, 2017, 8(2): e1398.
[4] HODGKIN J, ZELLAN J D , ALBERTSON D G. Identification of a candidate primary sex determination locus, fox-1, on the X chromosome of caenorhabditis elegans[J]. Development, 1994, 120(12): 3681-3689.
[5] WEYN-VANHENTENRYCK S M, FENG Huijuan, USTIANENKO D, et al. Precise temporal regulation of alternative splicing during neural development[J]. Nature Communication, 2018, 9(1): 2189.
[6] CARREIRA-ROSARIO A, BHARGAVA V, HILLEBRAND J, et al. Repression of Pumilio protein expression by Rbfox1 promotes germ cell differentiation[J]. Development Cell, 2016, 36(5): 562-571.
[7] VENABLES J P, BROSSEAU J P, GADEA G, et al. RBFOX2 is an important regulator of mesenchymal tissue-specific splicing in both normal and cancer tissues[J]. Molecular and Cellular Biology, 2013, 33(2): 396-405.
[8] YEO G W, COUFAL N G, LIANG T Y, et al. An RNA code for the FOX2 splicing regulator revealed by mapping RNA-protein interactions in stem cells[J]. Nature Structural & Molecular Biology, 2009, 16(2): 130-137.
[9] KUROYANAGI H. Fox-1 family of RNA-binding proteins[J]. Cell Molecular Science, 2009, 66(24): 3895-3907.
[10] AUWETER S D, FASAN R, REYMOND L, et al. Molecular basis of RNA recognition by the human alternative splicing factor fox-1[J]. The EMBO Journal, 2006, 25(1): 163-173.
[11] WEI Chaoliang, QIU Jinsong, ZHOU Yu, et al. Repression of the central splicing regulator RBFox2 is functionally linked to pressure overload-induced heart failure[J]. Cell Reports, 2015, 10(9): 1521-1533.
[12] HU Jing, GAO Chen, WEI Chaoliang, et al. RBFox2-miR-34a-Jph2 axis contributes to cardiac decompensation during heart failure[J]. Proceedings of the National Academy of Sciences of the United States of America, 2019, 116(13): 6172-6180.
[13] STETEFELD J, RUEGG M A. Structural and functional diversity generated by alternative mRNA splicing[J]. Trends in Biochemcal Sciences, 2005, 30(9): 515-521.
[14] WEYN-VANHENTENRYCK S M, MELE A, YAN Qinghong, et al. HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism[J]. Cell Reports, 2014, 6(6): 1139-1152.
[15] LOVCI M T, GHANEM D, MARR H, et al. Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges[J]. Nature Structure Molecular Biological, 2013, 20(12): 1434-1442.
[16] DAMIANOV A, YING Yi, LIN C H, et al. Rbfox proteins regulate splicing as part of a large multiprotein complex LASR[J]. Cell, 2016, 165(3): 606-619.
[17] YING Yi, WANG Xiaojun, VUONG C K, et al. Splicing activation by Rbfox requires self-aggregation through its tyrosine-rich domain[J]. Cell, 2017, 170(2): 312-323.
[18] MINOVITSKY S, GEE S L FAU-SCHOKRPUR S, et al. The splicing regulatory element, UGCAUG, is phylogenetically and spatially conserved in introns that flank tissue-specific alternative exons[J]. Nucleic Acids Research, 2005, 33(2): 714-724.
[19] JACKO M, WEYN-VANHENTENRYCK S M, SMERDON J W, et al. Rbfox splicing factors promote neuronal maturation and axon initial segment assembly[J]. Neuron, 2018, 97(4): 853-868.
[20] SINGH R K, KOLONIN A M, FIOROTTO M L, et al. Rbfox-splicing factors maintain skeletal muscle mass by regulating calpain3 and proteostasis[J]. Cell Reports, 2018, 24(1): 197-208.
[21] SAYED D, ABDELLATIF M. MicroRNAs in development and disease[J]. Physiological Reviews, 2011, 91(3): 827-887.
[22] CHEN Yu, ZUBOVIC L, YANG Fan, et al. Rbfox proteins regulate microRNA biogenesis by sequence-specific binding to their precursors and target downstream Dicer[J]. Nucleic Acids Research, 2016, 44(9): 4381-4395.
[23] KIM K K, YANG Yanqin, ZHU Jun, et al. Rbfox3 controls the biogenesis of a subset of microRNAs[J]. Nature Structural and Molecular Biology, 2014, 21(10): 901-910.
[24] RAY D, KAZAN H, COOK K B, et al. A compendium of RNA-binding motifs for decoding gene regulation[J]. Nature, 2013, 499(7457): 172-177.
[25] VERMA S K, DESHMUKH V, NUTTER C A, et al. Rbfox2 function in RNA metabolism is impaired in hypoplastic left heart syndrome patient hearts[J]. Scientific Reports, 2016, 6: 30896.
[26] KALSOTRA A, XIAO X, WARD A J, et al. A postnatal switch of CELF and MBNL proteins reprograms alternative splicing in the developing heart[J]. Proceedings of the National Academy of Sciences, 2008, 105(51): 20333-20338.
[27] GAO Chen, REN Shuxun, LEE J H, et al. RBFox1-mediated RNA splicing regulates cardiac hypertrophy and heart failure[J]. The Journal of Clinical Investigation, 2016, 126(1): 195-206.
[28] FRESE K S, MEDER B, KELLER A, et al. RNA splicing regulated by RBFOX1 is essential for cardiac function in zebrafish[J]. Journal of Cell Science, 2015, 128(16): 3030-3040.
[29] WANG Juejin, LI Guang, YU Dejie, et al. Characterization of CaV1.2 exon 33 heterozygous knockout mice and negative correlation between Rbfox1 and CaV1.2 exon 33 expressions in human heart failure[J]. Channels, 2018, 12(1): 51-57.
[30] ALLEN S E, TORO C P, ANDRADE A, et al. Cell-specific RNA binding protein Rbfox2 regulates CaV2.2 mRNA exon composition and CaV2.2 current size[J]. eNeuro, 2017, 4(5): e0332.
[31] PISTONI M, SHIUE L, CLINE M S, et al. Rbfox1 downregulation and altered Calpain 3 splicing by FRG1 in a mouse model of facioscapulohumeral muscular dystrophy (FSHD)[J]. PLoS Genetics, 2013, 9(1): e1003186.
[32] GEHMAN L T, STOILOV P, MAGUIRE J, et al. The splicing regulator Rbfox1 (A2BP1) controls neuronal excitation in the mammalian brain[J]. Nature Genetics, 2011, 43(7): 706-711.
[33] LIN Yisian, WANG Hanying, HUANG Defong, et al. Neuronal splicing regulator RBFOX3 (NeuN) regulates adult hippocampal neurogenesis and synaptogenesis[J]. PLoS One, 2016, 11(10): e0164164.
[34] PINTO D, PAGNAMENTA AT, KLEI L, et al. Functional impact of global rare copy number variation in autism spectrum disorders[J]. Nature, 2010, 466(7304): 368-372.
[35] SANDERS S J, ERCAN-SENCICEK A, HUS V, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism[J]. Neuron, 2011, 70(5): 863-885.
[36] LOVE J E, HAYDEN E J, ROHN T T. Alternative splicing in Alzheimer’s disease[J]. Journal of Parkinson’s Disease and Alzheimer’s Disease, 2015, 2(2). doi: 10.13188/2376-922X.1000010.
[37] LEE J A, DAMIANOV A, LIN C H, et al. Cytoplasmic Rbfox1 regulates the expression of synaptic and autism-related genes[J]. Neuron, 2016, 89(1): 113-128.
[38] ALKALLAS R, FISH L, GOODARZI H, et al. Inference of RNA decay rate from transcriptional profiling highlights the regulatory programs of Alzheimer’s disease[J]. Nature Communications, 2017, 8(1): 909.
[39] JUAN-MATEU J, RECH T H, VILLATE O, et al. Neuron-enriched RNA-binding proteins regulate pancreatic beta cell function and survival[J]. The Journal of Biological Chemistry, 2017, 292(8): 3466-3480.
[40] NUTTER C A, JAWORSKI E A, VERMA S K, et al. Dysregulation of RBFox2 is an early event in cardiac pathogenesis of diabetes[J]. Cell Reports, 2016, 15(10): 2200-2213.
[41] VERMA S K, DESHMUKH V, LIU P, et al. Reactivation of fetal splicing programs in diabetic hearts is mediated by protein kinase C signaling[J]. The Journal of Biological Chemistry, 2013, 288(49): 35372-35386.
[42] VENABLES J P, KLINCK R, KOH C, et al. Cancer-associated regulation of alternative splicing[J]. Nature Structural & Molecular Biology, 2009, 16: 670-676.
[43] LAPUK A, MARR H, Jakkula L, Pedro H, et al. Exon-level microarray analyses identify alternative splicing programs in breast cancer[J]. Molecular Cancer Research, 2010, 8(7): 961-974.
[44] HARVEY S E, XU Yilin, LIN Xiaodan, et al. Coregulation of alternative splicing by hnRNPM and ESRP1 during EMT[J]. RNA, 2018, 24(10): 1326-1338.
[45] LIU Tianze, WU Xiaojun, LI Yizhou, et al. RBFox3 Regulates the chemosensitivity of cancer cells to 5-fluorouracil via the PI3K/AKT, EMT and cytochrome-C/caspase pathways[J]. Cellular Physiology and Biochemistry, 2018, 46(4): 1365-1380.
[46] LIU Tianze, LI Wenbin, LU Wenjing, et al. RBFox3 Promotes tumor growth and progression via hTERT signaling and predicts a poor prognosis in hepatocellular carcinoma[J]. Theranostics, 2017, 7(12): 3138-3154.
[47] KIM Y E, KIM J O, PARK K S, et al. Transforming Growth factor-β-induced RBFOX3 inhibition promotes epithelial-mesenchymal transition of lung cancer cells[J]. Molecular Cells, 2016, 39(8): 625-630.
[48] GALLAGHER T L, ARRIBERE J A, GEURTS P A, et al. Rbfox-regulated alternative splicing is critical for zebrafish cardiac and skeletal muscle functions[J]. Developmental Biology, 2011, 359(2): 251-261.
[49] SINGH R K, XIA Zheng, BLAND C S, et al. Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis[J]. Molecular Cell, 2014, 55(4): 592-603.
[50] PEDROTTI S, GIUDICE J, DAGNINO-ACOSTA A, et al. The RNA-binding protein Rbfox1 regulates splicing required for skeletal muscle structure and function[J]. Human Molecular Genetics, 2015, 24(8): 2360-2374.
[51] GU Lei, BOK D, YU Fei, et al. Downregulation of splicing regulator RBFOX1 compromises visual depth perception[J]. PLoS One, 2018, 13(7): e0200417.
[52] MURPHY P A, BUTTY V L, BOUTZ P L, et al. Alternative RNA splicing in the endothelium mediated in part by Rbfox2 regulates the arterial response to low flow[J]. eLife, 2018, 7: e29494.


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 Zhao Yunyan,Li Zhong,Chen Danni,et al.Systematic regulatory network of gamma-aminobutyric acid receptor genes[J].Journal of Shenzhen University Science and Engineering,2015,32(5):128.[doi:10.3724/SP.J.1249.2015.02128]
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 LOU Sulin,ZHU Xiulan,ZENG Zhiyong,et al.Bioinformatics analysis of Dunaliella microRNAs by high-throughput sequencing[J].Journal of Shenzhen University Science and Engineering,2018,35(5):331.[doi:10.3724/SP.J.1249.2018.04331]
 LOU Sulin,LIN Xin,HUANG Simin,et al.Cloning and bioinformatics analysis of CrDRBs in Chlamydomonas reinhardtii[J].Journal of Shenzhen University Science and Engineering,2018,35(5):523.[doi:10.3724/SP.J.1249.2018.05523]
 LI Lin,LUO Linlin,et al.Establishment and evaluation of a method for rapid extraction of plant genomic DNA[J].Journal of Shenzhen University Science and Engineering,2020,37(5):1.[doi:10.3724/SP.J.1249.2020.01001]
 HOU Kaiyue,LOU Sulin,ZENG Zhiyong,et al.Prediction and identification of sulfur-responding circular RNA in Chlamydomonas reinhardtii[J].Journal of Shenzhen University Science and Engineering,2020,37(5):221.[doi:10.3724/SP.J.1249.2020.03221]
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Foundation:National Natural Science Foundation of China (81770227); Shenzhen Science and Technology Reasearch Faundation (JCY20180507182239272)
Corresponding author:Professor WEI Chaoliang. E-mail: weicl@szu.edu.cn
Citation:WEI Chaoliang, XIA Ming, GU Mingyao. RBFox family proteins in function and disease regulation[J]. Journal of Shenzhen University Science and Engineering, 2020, 37(5): 514-520.(in Chinese)
基金项目:国家自然科学基金资助项目(81770227);深圳市科技计划资助项目 (JCY20180507182239272)
作者简介:魏朝亮(1979—),男,深圳大学教授.研究方向:钙信号与运动迁移.E-mail: weicl@szu.edu.cn
引文:魏朝亮,夏明,谷明瑶.功能与疾病中的RBFox蛋白家族[J]. 深圳大学学报理工版,2020,37(5):514-520.
更新日期/Last Update: 2020-07-26