Localization and translocation of mature miRNAs

Authors

DOI:

https://doi.org/10.22141/2224-0551.16.7.2021.244583

Keywords:

microRNA, microRNA translocation, P-bodies, microRNA localization, RNA-induced silencing complex (RISC), review

Abstract

The scientific review shows the ways of nuclear import and export of miRNAs in the cell. The authors present a clear and accessible scheme of microRNA translocation in the cell. The article shows that the main site of localization in the cytoplasm of cells of the RISC complex and its components, including miRNAs, are processing P-cells. The authors cite the fact that Argonaute proteins — signature components of the effector complex of RISC RNA interference — are localized in mammalian P-bodies. It is shown that proteins of the karyopherin family mediate the translocation of miRISC into the cell nucleus. These proteins recognize nuclear localization sequences (NLS) in the amino acid sequences of proteins and actively transport these proteins through the pores of the cell’s nuclear membrane. It is emphasized that in addition to non-selective mechanisms of nuclear import of miRNAs, there are transport mechanisms that carry certain miRNAs across the cell membrane. Some miRNAs are presented, which are mainly loca­lized in the nucleus of a certain type of cell. Scientists believe that much of the nucleus miRNA is concentrated in polysomes. Export of nuclear pool microRNA into the cytoplasm of the cell occurs with the help of export 1. Thus, in the cytoplasm of the cell, mature forms of microRNA accumulate, some of which are translocated to the cell nucleus or the extracellular space. Assembly of the miRISC complex is carried out in the cytoplasm of the cell, and only after the formation of the complex, it is imported into the cell nucleus. The spectrum of exosome-associated miRNAs can be a highly important diagnostic criterion for some nosologies, and exosomes containing certain miRNAs can be used for targeted therapy of specific diseases. To write the article, information was searched using databases Scopus, Web of Science, MedLine, PubMed, Google Scholar, EMBASE, Global Health, The Cochrane Library, CyberLeninka.

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References

Akers JC, Gonda D, Kim R, Carter BS, Chen CC. Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies. J Neurooncol. 2013 May;113(1):1-11. doi:10.1007/s11060-013-1084-8.

Arroyo JD, Chevillet JR, Kroh EM, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):5003-8. doi:10.1073/pnas.1019055108.

Barrès C, Blanc L, Bette-Bobillo P, et al. Galectin-5 is bound onto the surface of rat reticulocyte exosomes and modulates vesicle uptake by macrophages. Blood. 2010 Jan 21;115(3):696-705. doi:10.1182/blood-2009-07-231449.

Bayraktar R, Van Roosbroeck K, Calin GA. Cell-to-cell communication: microRNAs as hormones. Mol Oncol. 2017 Dec;11(12):1673-1686. doi:10.1002/1878-0261.12144.

Bhatnagar S, Schorey JS. Exosomes released from infected macrophages contain Mycobacterium avium glycopeptidolipids and are proinflammatory. J Biol Chem. 2007 Aug 31;282(35):25779-89. doi:10.1074/jbc.M702277200.

Bhome R, Del Vecchio F, Lee GH, et al. Exosomal microRNAs (exomiRs): Small molecules with a big role in cancer. Cancer Lett. 2018 Apr 28;420:228-235. doi:10.1016/j.canlet.2018.02.002.

Blandford SN, Galloway DA, Moore CS. The roles of extracellular vesicle microRNAs in the central nervous system. Glia. 2018 Nov;66(11):2267-2278. doi:10.1002/glia.23445.

Bolukbasi MF, Mizrak A, Ozdener GB, et al. miR-1289 and "Zipcode"-like Sequence Enrich mRNAs in Microvesicles. Mol Ther Nucleic Acids. 2012 Feb 7;1(2):e10. doi:10.1038/mtna.2011.2.

Carretero-González A, Otero I, Carril-Ajuria L, de Velasco G, Manso L. Exosomes: Definition, Role in Tumor Development and Clinical Implications. Cancer Microenviron. 2018 Jun;11(1):13-21. doi:10.1007/s12307-018-0211-7.

Chen L, Chen R, Kemper S, Cong M, You H, Brigstock DR. Therapeutic effects of serum extracellular vesicles in liver fibrosis. J Extracell Vesicles. 2018 Apr 17;7(1):1461505. doi:10.1080/20013078.2018.1461505.

da Silveira JC, de Ávila ACFCM, Garrett HL, Bruemmer JE, Winger QA, Bouma GJ. Cell-secreted vesicles containing microRNAs as regulators of gamete maturation. J Endocrinol. 2018 Jan;236(1):R15-R27. doi:10.1530/JOE-17-0200.

de Jong OG, Verhaar MC, Chen Y, et al. Cellular stress conditions are reflected in the protein and RNA content of endothelial cell-derived exosomes. J Extracell Vesicles. 2012 Apr 16;1. doi:10.3402/jev.v1i0.18396.

Deng H, Sun C, Sun Y, et al. Lipid, Protein, and MicroRNA Composition Within Mesenchymal Stem Cell-Derived Exosomes. Cell Reprogram. 2018 Jun;20(3):178-186. doi:10.1089/cell.2017.0047.

Devhare PB, Ray RB. Extracellular vesicles: Novel mediator for cell to cell communications in liver pathogenesis. Mol Aspects Med. 2018 Apr;60:115-122. doi:10.1016/j.mam.2017.11.001.

Gagnon KT, Li L, Chu Y, Janowski BA, Corey DR. RNAi factors are present and active in human cell nuclei. Cell Rep. 2014 Jan 16;6(1):211-21. doi:10.1016/j.celrep.2013.12.013.

Gallagher C, Ramos A. Joining the dots - protein-RNA interactions mediating local mRNA translation in neurons. FEBS Lett. 2018 Sep;592(17):2932-2947. doi:10.1002/1873-3468.13121.

Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol. 2009 Sep;11(9):1143-9. doi:10.1038/ncb1929.

Groot M, Lee H. Sorting Mechanisms for MicroRNAs into Extracellular Vesicles and Their Associated Diseases. Cells. 2020 Apr 22;9(4):1044. doi:10.3390/cells9041044.

Hao S, Bai O, Li F, Yuan J, Laferte S, Xiang J. Mature dendritic cells pulsed with exosomes stimulate efficient cytotoxic T-lymphocyte responses and antitumour immunity. Immunology. 2007 Jan;120(1):90-102. doi:10.1111/j.1365-2567.2006.02483.x.

Heijnen H, van der Sluijs P. Platelet secretory behaviour: as diverse as the granules … or not? J Thromb Haemost. 2015 Dec;13(12):2141-51. doi:10.1111/jth.13147.

Hess C, Sadallah S, Hefti A, Landmann R, Schifferli JA. Ectosomes released by human neutrophils are specialized functional units. J Immunol. 1999 Oct 15;163(8):4564-73.

Hwang HW, Wentzel EA, Mendell JT. A hexanucleotide element directs microRNA nuclear import. Science. 2007 Jan 5;315(5808):97-100. doi:10.1126/science.1136235.

Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987 Jul 5;262(19):9412-20.

Kamenska A, Simpson C, Vindry C, et al. The DDX6-4E-T interaction mediates translational repression and P-body assembly. Nucleic Acids Res. 2016 Jul 27;44(13):6318-34. doi:10.1093/nar/gkw565.

Katahira J, Yoneda Y. Nucleocytoplasmic transport of microRNAs and related small RNAs. Traffic. 2011 Nov;12(11):1468-74. doi:10.1111/j.1600-0854.2011.01211.x.

Kim KM, Abdelmohsen K, Mustapic M, Kapogiannis D, Gorospe M. RNA in extracellular vesicles. Wiley Interdiscip Rev RNA. 2017 Jul;8(4):10.1002/wrna.1413. doi:10.1002/wrna.1413.

Koppers-Lalic D, Hackenberg M, Bijnsdorp IV, et al. Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep. 2014 Sep 25;8(6):1649-1658. doi:10.1016/j.celrep.2014.08.027.

Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. 2010 Jun 4;285(23):17442-52. doi:10.1074/jbc.M110.107821.

LeBleu VS, Kalluri R. Exosomes as a Multicomponent Biomarker Platform in Cancer. Trends Cancer. 2020 Sep;6(9):767-774. doi:10.1016/j.trecan.2020.03.007.

Leone DA, Rees AJ, Kain R. Dendritic cells and routing cargo into exosomes. Immunol Cell Biol. 2018 May 24. doi:10.1111/imcb.12170.

Li S, Yao J, Xie M, Liu Y, Zheng M. Exosomal miRNAs in hepatocellular carcinoma development and clinical responses. J Hematol Oncol. 2018 Apr 11;11(1):54. doi:10.1186/s13045-018-0579-3.

Li T, Yan Y, Wang B, et al. Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev. 2013 Mar 15;22(6):845-54. doi:10.1089/scd.2012.0395.

Liu H, Lei C, He Q, Pan Z, Xiao D, Tao Y. Nuclear functions of mammalian MicroRNAs in gene regulation, immunity and cancer. Mol Cancer. 2018 Feb 22;17(1):64. doi:10.1186/s12943-018-0765-5.

Lu J, Wu J, Tian J, Wang S. Role of T cell-derived exosomes in immunoregulation. Immunol Res. 2018 Jun;66(3):313-322. doi:10.1007/s12026-018-9000-0.

Luarte A, Cisternas P, Caviedes A, et al. Astrocytes at the Hub of the Stress Response: Potential Modulation of Neurogenesis by miRNAs in Astrocyte-Derived Exosomes. Stem Cells Int. 2017;2017:1719050. doi:10.1155/2017/1719050.

Luo Y, Na Z, Slavoff SA. P-Bodies: Composition, Properties, and Functions. Biochemistry. 2018 May 1;57(17):2424-2431. doi:10.1021/acs.biochem.7b01162.

Maji S, Matsuda A, Yan IK, Parasramka M, Patel T. Extracellular vesicles in liver diseases. Am J Physiol Gastrointest Liver Physiol. 2017 Mar 1;312(3):G194-G200. doi:10.1152/ajpgi.00216.2016.

Makarova J, Turchinovich A, Shkurnikov M, Tonevitsky A. Extracellular miRNAs and Cell-Cell Communication: Problems and Prospects. Trends Biochem Sci. 2021 Aug;46(8):640-651. doi:10.1016/j.tibs.2021.01.007.

Makarova JA, Shkurnikov MU, Wicklein D, et al. Intracellular and extracellular microRNA: An update on localization and biological role. Prog Histochem Cytochem. 2016 Nov;51(3-4):33-49. doi:10.1016/j.proghi.2016.06.001.

Masyuk AI, Masyuk TV, Larusso NF. Exosomes in the pathogenesis, diagnostics and therapeutics of liver diseases. J Hepatol. 2013 Sep;59(3):621-5. doi:10.1016/j.jhep.2013.03.028.

McLellan AD. Exosome release by primary B cells. Crit Rev Immunol. 2009;29(3):203-17. doi:10.1615/critrevimmunol.v29.i3.20.

Meldolesi J. Exosomes and Ectosomes in Intercellular Communication. Curr Biol. 2018 Apr 23;28(8):R435-R444. doi:10.1016/j.cub.2018.01.059.

Nishi K, Nishi A, Nagasawa T, Ui-Tei K. Human TNRC6A is an Argonaute-navigator protein for microRNA-mediated gene silencing in the nucleus. RNA. 2013 Jan;19(1):17-35. doi:10.1261/rna.034769.112.

Nong K, Wang W, Niu X, et al. Hepatoprotective effect of exosomes from human-induced pluripotent stem cell-derived mesenchymal stromal cells against hepatic ischemia-reperfusion injury in rats. Cytotherapy. 2016 Dec;18(12):1548-1559. doi:10.1016/j.jcyt.2016.08.002.

Paris Z. Nuclear tRNA export in trypanosomes: a journey full of twists and turns guided by tRNA modifications. Parasitology. 2021 Sep;148(10):1219-1222. doi:10.1017/S0031182021000482.

Polanco JC, Li C, Durisic N, Sullivan R, Götz J. Exosomes taken up by neurons hijack the endosomal pathway to spread to interconnected neurons. Acta Neuropathol Commun. 2018 Feb 15;6(1):10. doi:10.1186/s40478-018-0514-4.

Politz JC, Hogan EM, Pederson T. MicroRNAs with a nucleolar location. RNA. 2009 Sep;15(9):1705-15. doi:10.1261/rna.1470409.

Qiu H, Shi S, Wang S, Peng H, Ding SJ, Wang L. Proteomic Profiling Exosomes from Vascular Smooth Muscle Cell. Proteomics Clin Appl. 2018 Sep;12(5):e1700097. doi:10.1002/prca.201700097.

Reyes-Gutierrez P, Ritland Politz JC, Pederson T. A mRNA and cognate microRNAs localize in the nucleolus. Nucleus. 2014;5(6):636-42. doi:10.4161/19491034.2014.990864.

Roberts T.C. The MicroRNA Biology of the Mammalian Nucleus. Mol Ther Nucleic Acids. 2014 Aug 19;3:e188. doi:10.1038/mtna.2014.40.

Royo F, Moreno L, Mleczko J, et al. Hepatocyte-secreted extracellular vesicles modify blood metabolome and endothelial function by an arginase-dependent mechanism. Sci Rep. 2017 Feb 17;7:42798. doi:10.1038/srep42798.

Royo F, Schlangen K, Palomo L, et al. Transcriptome of extracellular vesicles released by hepatocytes. PLoS One. 2013 Jul 11;8(7):e68693. doi:10.1371/journal.pone.0068693.

Ruivo CF, Adem B, Silva M, Melo SA. The Biology of Cancer Exosomes: Insights and New Perspectives. Cancer Res. 2017 Dec 1;77(23):6480-6488. doi:10.1158/0008-5472.CAN-17-0994.

Salehi M, Sharifi M. Exosomal miRNAs as novel cancer biomarkers: Challenges and opportunities. J Cell Physiol. 2018 Sep;233(9):6370-6380. doi:10.1002/jcp.26481.

Sankaranarayanan M, Emenecker RJ, Jahnel M, et al. The arrested state of processing bodies supports mRNA regulation in early development. bioRxiv. 2021;03(16):435709. doi:10.1101/2021.03.16.435709.

Saunderson SC, Dunn AC, Crocker PR, McLellan AD. CD169 mediates the capture of exosomes in spleen and lymph node. Blood. 2014 Jan 9;123(2):208-16. doi:10.1182/blood-2013-03-489732.

Schraivogel D, Schindler SG, Danner J, et al. Importin-β facilitates nuclear import of human GW proteins and balances cytoplasmic gene silencing protein levels. Nucleic Acids Res. 2015 Sep 3;43(15):7447-61. doi:10.1093/nar/gkv705.

Shapouri F, Saeidi S, de Iongh RU, et al. Tob1 is expressed in developing and adult gonads and is associated with the P-body marker, Dcp2. Cell Tissue Res. 2016 May;364(2):443-51. doi:10.1007/s00441-015-2328-z.

Smythies LE, Smythies JR. Exosomes in the gut. Front Immunol. 2014 Mar 17;5:104. doi:10.3389/fimmu.2014.00104.

Stahl PD, Raposo G. Exosomes and extracellular vesicles: the path forward. Essays Biochem. 2018 May 15;62(2):119-124. doi:10.1042/EBC20170088.

Stalder L, Heusermann W, Sokol L, et al. The rough endoplasmatic reticulum is a central nucleation site of siRNA-mediated RNA silencing. EMBO J. 2013 Apr 17;32(8):1115-27. doi:10.1038/emboj.2013.52.

Takahashi Y, Nishikawa M, Shinotsuka H, et al. Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. J Biotechnol. 2013 May 20;165(2):77-84. doi:10.1016/j.jbiotec.2013.03.013.

Tan CY, Lai RC, Wong W, Dan YY, Lim SK, Ho HK. Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther. 2014 Jun 10;5(3):76. doi:10.1186/scrt465.

Tkach M, Théry C. Communication by Extracellular Vesicles: Where We Are and Where We Need to Go. Cell. 2016 Mar 10;164(6):1226-1232. doi:10.1016/j.cell.2016.01.043.

Tucci M, Mannavola F, Passarelli A, Stucci LS, Cives M, Silvestris F. Exosomes in melanoma: a role in tumor progression, metastasis and impaired immune system activity. Oncotarget. 2018 Apr 17;9(29):20826-20837. doi:10.18632/oncotarget.24846.

Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ, Lötvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007 Jun;9(6):654-9. doi:10.1038/ncb1596.

Varela-Eirin M, Varela-Vazquez A, Rodríguez-Candela Mateos M, et al. Recruitment of RNA molecules by connexin RNA-binding motifs: Implication in RNA and DNA transport through microvesicles and exosomes. Biochim Biophys Acta Mol Cell Res. 2017 Apr;1864(4):728-736. doi:10.1016/j.bbamcr.2017.02.001.

Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 2013;4:2980. doi:10.1038/ncomms3980.

Vukman KV, Försönits A, Oszvald Á, Tóth EÁ, Buzás EI. Mast cell secretome: Soluble and vesicular components. Semin Cell Dev Biol. 2017 Jul;67:65-73. doi:10.1016/j.semcdb.2017.02.002.

Waldenström A, Gennebäck N, Hellman U, Ronquist G. Cardiomyocyte microvesicles contain DNA/RNA and convey biological messages to target cells. PLoS One. 2012;7(4):e34653. doi:10.1371/journal.pone.0034653.

Wang S, Wang JQ, Lv XW. Exosomal miRNAs as biomarkers in the diagnosis of liver disease. Biomark Med. 2017 May;11(6):491-501. doi:10.2217/bmm-2017-0011.

Wei Y, Li L, Wang D, Zhang CY, Zen K. Importin 8 regulates the transport of mature microRNAs into the cell nucleus. J Biol Chem. 2014 Apr 11;289(15):10270-10275. doi:10.1074/jbc.C113.541417.

Willekens FL, Werre JM, Kruijt JK, et al. Liver Kupffer cells rapidly remove red blood cell-derived vesicles from the circulation by scavenger receptors. Blood. 2005 Mar 1;105(5):2141-5. doi:10.1182/blood-2004-04-1578.

Yáñez-Mó M, Siljander PR, Andreu Z, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles. 2015 May 14;4:27066. doi:10.3402/jev.v4.27066.

Yu X, Odenthal M, Fries JW. Exosomes as miRNA Carriers: Formation-Function-Future. Int J Mol Sci. 2016 Dec 2;17(12):2028. doi:10.3390/ijms17122028.

Zhang J, Li S, Li L, et al. Exosome and exosomal microRNA: trafficking, sorting, and function. Genomics Proteomics Bioinformatics. 2015 Feb;13(1):17-24. doi:10.1016/j.gpb.2015.02.001.

Zhang T, Tan P, Wang L, et al. RNALocate: a resource for RNA subcellular localizations. Nucleic Acids Res. 2017 Jan 4;45(D1):D135-D138. doi:10.1093/nar/gkw728.

Zhang W, Jiang X, Bao J, Wang Y, Liu H, Tang L. Exosomes in Pathogen Infections: A Bridge to Deliver Molecules and Link Functions. Front Immunol. 2018 Feb 12;9:90. doi:10.3389/fimmu.2018.00090.

Zhu Q, Heon M, Zhao Z, He M. Microfluidic engineering of exosomes: editing cellular messages for precision therapeutics. Lab Chip. 2018 Jun 12;18(12):1690-1703. doi:10.1039/c8lc00246k.

Published

2022-01-19

How to Cite

Abaturov, A., & Babуch V. (2022). Localization and translocation of mature miRNAs. CHILD`S HEALTH, 16(7), 498–507. https://doi.org/10.22141/2224-0551.16.7.2021.244583

Issue

Section

Theoretical Medicine

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