1932

Abstract

The subcellular localization of a biopolymer often informs its function. RNA is traditionally confined to the cytosolic and nuclear spaces, where it plays critical and conserved roles across nearly all biochemical processes. Our recent observation of cell surface glycoRNAs may further explain the extracellular role of RNA. While cellular membranes are efficient gatekeepers of charged polymers such as RNAs, a large body of research has demonstrated the accumulation of specific RNA species outside of the cell, termed extracellular RNAs (exRNAs). Across various species and forms of life, protein pores have evolved to transport RNA across membranes, thus providing a mechanistic path for exRNAs to achieve their extracellular topology. Here, we review types of exRNAs and the pores capable of RNA transport to provide a logical and testable path toward understanding the biogenesis and regulation of cell surface glycoRNAs.

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2023-08-25
2024-05-06
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Literature Cited

  1. 1.
    Abels ER, Breakefield XO. 2016. Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell. Mol. Neurobiol. 36:301–12
    [Google Scholar]
  2. 2.
    Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH et al. 2007. XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol. Cell 27:53–66
    [Google Scholar]
  3. 3.
    Aizawa S, Fujiwara Y, Contu VR, Hase K, Takahashi M et al. 2016. Lysosomal putative RNA transporter SIDT2 mediates direct uptake of RNA by lysosomes. Autophagy 12:565–78
    [Google Scholar]
  4. 4.
    Albanese M, Chen Y-FA, Hüls C, Gärtner K, Tagawa T et al. 2021. MicroRNAs are minor constituents of extracellular vesicles that are rarely delivered to target cells. PLOS Genet. 17:e1009951
    [Google Scholar]
  5. 5.
    Allen RM, Zhao S, Ramirez Solano MA, Zhu W, Michell DL et al. 2018. Bioinformatic analysis of endogenous and exogenous small RNAs on lipoproteins. J. Extracell. Vesicles 7:1506198
    [Google Scholar]
  6. 6.
    Al-Mulla HMN, Turrell L, Smith NM, Payne L, Baliji S et al. 2014. Competitive fitness in coronaviruses is not correlated with size or number of double-membrane vesicles under reduced-temperature growth conditions. mBio 5:e01107–13
    [Google Scholar]
  7. 7.
    Andersen OS, Koeppe RE. 2007. Bilayer thickness and membrane protein function: an energetic perspective. Annu. Rev. Biophys. Biomol. Struct. 36:107–30
    [Google Scholar]
  8. 8.
    Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR et al. 1981. Sequence and organization of the human mitochondrial genome. Nature 290:457–65
    [Google Scholar]
  9. 9.
    Araiso Y, Tsutsumi A, Qiu J, Imai K, Shiota T et al. 2019. Structure of the mitochondrial import gate reveals distinct preprotein paths. Nature 575:395–401
    [Google Scholar]
  10. 10.
    Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC et al. 2011. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. PNAS 108:5003–8
    [Google Scholar]
  11. 11.
    Benner SA. 1988. Extracellular “communicator RNA. .” FEBS Lett. 233:225–28
    [Google Scholar]
  12. 12.
    Blobel G, Walter P, Chang CN, Goldman BM, Erickson AH, Lingappa VR. 1979. Translocation of proteins across membranes: the signal hypothesis and beyond. Symp. Soc. Exp. Biol. 33:9–36
    [Google Scholar]
  13. 13.
    Bogdanov AA, Dontsova OA, Dokudovskaya SS, Lavrik IN. 1995. Structure and function of 5S rRNA in the ribosome. Biochem. Cell. Biol. 73:869–76
    [Google Scholar]
  14. 14.
    Böhni PC, Daum G, Schatz G. 1983. Import of proteins into mitochondria. Partial purification of a matrix-located protease involved in cleavage of mitochondrial precursor polypeptides. J. Biol. Chem. 258:4937–43
    [Google Scholar]
  15. 15.
    Borowski LS, Dziembowski A, Hejnowicz MS, Stepien PP, Szczesny RJ. 2013. Human mitochondrial RNA decay mediated by PNPase-hSuv3 complex takes place in distinct foci. Nucleic Acids Res. 41:1223–40
    [Google Scholar]
  16. 16.
    Bretscher MS. 1973. Membrane structure: some general principles. Science 181:622–29
    [Google Scholar]
  17. 17.
    Budker VG, Kazatchkov YA, Naumova LP. 1978. Polynucleotides adsorb on mitochondrial and model lipid membranes in the presence of bivalent cations. FEBS Lett. 95:143–46
    [Google Scholar]
  18. 18.
    Cha DJ, Franklin JL, Dou Y, Liu Q, Higginbotham JN et al. 2015. KRAS-dependent sorting of miRNA to exosomes. eLife 4:e07197
    [Google Scholar]
  19. 19.
    Chakrabortty SK, Prakash A, Nechooshtan G, Hearn S, Gingeras TR. 2015. Extracellular vesicle-mediated transfer of processed and functional RNY5 RNA. RNA 21:1966–79
    [Google Scholar]
  20. 20.
    Chang DD, Clayton DA. 1987. A mammalian mitochondrial RNA processing activity contains nucleus-encoded RNA. Science 235:1178–84
    [Google Scholar]
  21. 21.
    Chang G, Yang R, Cao Y, Nie A, Gu X, Zhang H. 2016. SIDT2 is involved in the NAADP-mediated release of calcium from insulin secretory granules. J. Mol. Endocrinol. 56:249–59
    [Google Scholar]
  22. 22.
    Chen H-W, Rainey RN, Balatoni CE, Dawson DW, Troke JJ et al. 2006. Mammalian polynucleotide phosphorylase is an intermembrane space RNase that maintains mitochondrial homeostasis. Mol. Cell. Biol. 26:8475–87
    [Google Scholar]
  23. 23.
    Chen Q, Yan M, Cao Z, Li X, Zhang Y et al. 2016. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351:397–400
    [Google Scholar]
  24. 24.
    Chen X, Gu X, Zhang H. 2018. Sidt2 regulates hepatocellular lipid metabolism through autophagy. J. Lipid Res. 59:404–15
    [Google Scholar]
  25. 25.
    Chen X, Liang H, Zhang J, Zen K, Zhang C-Y. 2013. MicroRNAs are ligands of Toll-like receptors. RNA 19:737–39
    [Google Scholar]
  26. 26.
    Chevillet JR, Kang Q, Ruf IK, Briggs HA, Vojtech LN et al. 2014. Quantitative and stoichiometric analysis of the microRNA content of exosomes. PNAS 111:14888–93
    [Google Scholar]
  27. 27.
    Contu VR, Hase K, Kozuka-Hata H, Oyama M, Fujiwara Y et al. 2017. Lysosomal targeting of SIDT2 via multiple YxxΦ motifs is required for SIDT2 function in the process of RNautophagy. J. Cell Sci. 130:2843–53
    [Google Scholar]
  28. 28.
    Cox JS, Shamu CE, Walter P. 1993. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 73:1197–1206
    [Google Scholar]
  29. 29.
    Dhir A, Dhir S, Borowski LS, Jimenez L, Teitell M et al. 2018. Mitochondrial double-stranded RNA triggers antiviral signalling in humans. Nature 560:238–42
    [Google Scholar]
  30. 30.
    Driedonks TAP, Nolte-’t Hoen ENM. 2018. Circulating Y-RNAs in extracellular vesicles and ribonucleoprotein complexes; implications for the immune system. Front. Immunol. 9:3164
    [Google Scholar]
  31. 31.
    Duxbury MS, Ashley SW, Whang EE. 2005. RNA interference: a mammalian SID-1 homologue enhances siRNA uptake and gene silencing efficacy in human cells. Biochem. Biophys. Res. Commun. 331:459–63
    [Google Scholar]
  32. 32.
    El-Mogy M, Lam B, Haj-Ahmad TA, McGowan S, Yu D et al. 2018. Diversity and signature of small RNA in different bodily fluids using next generation sequencing. BMC Genom. 19:408
    [Google Scholar]
  33. 33.
    Engel KL, Lo H-YG, Goering R, Li Y, Spitale RC, Taliaferro JM. 2022. Analysis of subcellular transcriptomes by RNA proximity labeling with Halo-seq. Nucleic Acids Res. 50:e24
    [Google Scholar]
  34. 34.
    Entelis N, Brandina I, Kamenski P, Krasheninnikov IA, Martin RP, Tarassov I. 2006. A glycolytic enzyme, enolase, is recruited as a cofactor of tRNA targeting toward mitochondria in Saccharomyces cerevisiae. Genes Dev. 20:1609–20
    [Google Scholar]
  35. 35.
    Entelis NS, Kolesnikova OA, Martin RP, Tarassov IA. 2001. RNA delivery into mitochondria. Adv. Drug Deliv. Rev. 49:199–215
    [Google Scholar]
  36. 36.
    Fabbiano F, Corsi J, Gurrieri E, Trevisan C, Notarangelo M, D'Agostino VG 2020. RNA packaging into extracellular vesicles: an orchestra of RNA-binding proteins?. J. Extracell. Vesicles 10:e12043
    [Google Scholar]
  37. 37.
    Fabbri M, Paone A, Calore F, Galli R, Gaudio E et al. 2012. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. PNAS 109:E2110–16
    [Google Scholar]
  38. 38.
    Fazal FM, Han S, Parker KR, Kaewsapsak P, Xu J et al. 2019. Atlas of subcellular RNA localization revealed by APEX-seq. Cell 178:473–90.e26
    [Google Scholar]
  39. 39.
    Feinberg EH, Hunter CP. 2003. Transport of dsRNA into cells by the transmembrane protein SID-1. Science 301:1545–47
    [Google Scholar]
  40. 40.
    Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. 1998. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–11
    [Google Scholar]
  41. 41.
    Flynn RA, Pedram K, Malaker SA, Batista PJ, Smith BAH et al. 2021. Small RNAs are modified with N-glycans and displayed on the surface of living cells. Cell 184:3109–24.e22
    [Google Scholar]
  42. 42.
    Fujiwara Y, Kabuta C, Sano T, Murayama S, Saito Y, Kabuta T. 2022. Pathology-associated change in levels and localization of SIDT2 in postmortem brains of Parkinson's disease and dementia with Lewy bodies patients. Neurochem. Int. 152:105243
    [Google Scholar]
  43. 43.
    Galvanin A, Dostert G, Ayadi L, Marchand V, Velot É, Motorin Y. 2019. Diversity and heterogeneity of extracellular RNA in human plasma. Biochimie 164:22–36
    [Google Scholar]
  44. 44.
    Gao J, Zhang Y, Yu C, Tan F, Wang L. 2016. Spontaneous nonalcoholic fatty liver disease and ER stress in Sidt2 deficiency mice. Biochem. Biophys. Res. Commun. 476:326–32
    [Google Scholar]
  45. 45.
    Garcia M, Delaveau T, Goussard S, Jacq C. 2010. Mitochondrial presequence and open reading frame mediate asymmetric localization of messenger RNA. EMBO Rep. 11:285–91
    [Google Scholar]
  46. 46.
    Geekiyanage H, Rayatpisheh S, Wohlschlegel JA, Brown R, Ambros V 2020. Extracellular microRNAs in human circulation are associated with miRISC complexes that are accessible to anti-AGO2 antibody and can bind target mimic oligonucleotides. PNAS 117:24213–23
    [Google Scholar]
  47. 47.
    Godoy PM, Bhakta NR, Barczak AJ, Cakmak H, Fisher S et al. 2018. Large differences in small RNA composition between human biofluids. Cell Rep. 25:1346–58
    [Google Scholar]
  48. 48.
    Gruner HN, McManus MT. 2021. Examining the evidence for extracellular RNA function in mammals. Nat. Rev. Genet. 22:448–58
    [Google Scholar]
  49. 49.
    Gupta SK, Haigh BJ, Griffin FJ, Wheeler TT. 2013. The mammalian secreted RNases: mechanisms of action in host defence. Innate Immun. 19:86–97
    [Google Scholar]
  50. 50.
    Happel C, Ganguly A, Tagle DA. 2020. Extracellular RNAs as potential biomarkers for cancer. J. Cancer Metastasis Treat. 6:32
    [Google Scholar]
  51. 51.
    Hase K, Contu VR, Kabuta C, Sakai R, Takahashi M et al. 2020. Cytosolic domain of SIDT2 carries an arginine-rich motif that binds to RNA/DNA and is important for the direct transport of nucleic acids into lysosomes. Autophagy 16:1974–88
    [Google Scholar]
  52. 52.
    Hill K, Model K, Ryan MT, Dietmeier K, Martin F et al. 1998. Tom40 forms the hydrophilic channel of the mitochondrial import pore for preproteins. Nature 395:516–21
    [Google Scholar]
  53. 53.
    Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS. 2009. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J. Cell Biol. 186:323–31
    [Google Scholar]
  54. 54.
    Hollien J, Weissman JS. 2006. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313:104–7
    [Google Scholar]
  55. 55.
    Hoy AM, Buck AH. 2012. Extracellular small RNAs: What, where, why?. Biochem. Soc. Trans. 40:886–90
    [Google Scholar]
  56. 56.
    Huang N, Fan X, Zaleta-Rivera K, Nguyen TC, Zhou J et al. 2020. Natural display of nuclear-encoded RNA on the cell surface and its impact on cell interaction. Genome Biol. 21:225
    [Google Scholar]
  57. 57.
    Hunter CP, Winston WM, Molodowitch C, Feinberg EH, Shih J et al. 2006. Systemic RNAi in Caenorhabditis elegans. Cold Spring Harb. Symp. Quant. Biol. 71:95–100
    [Google Scholar]
  58. 58.
    Hur S. 2019. Double-stranded RNA sensors and modulators in innate immunity. Annu. Rev. Immunol. 37:349–75
    [Google Scholar]
  59. 59.
    Janas T, Janas T, Yarus M. 2006. Specific RNA binding to ordered phospholipid bilayers. Nucleic Acids Res. 34:2128–36
    [Google Scholar]
  60. 60.
    Janas T, Janas T, Yarus M. 2012. Human tRNASec associates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers. RNA 18:2260–68
    [Google Scholar]
  61. 61.
    Jones R, Bragagnolo G, Arranz R, Reguera J. 2021. Capping pores of alphavirus nsP1 gate membranous viral replication factories. Nature 589:615–19
    [Google Scholar]
  62. 62.
    Jose AM, Smith JJ, Hunter CP. 2009. Export of RNA silencing from C. elegans tissues does not require the RNA channel SID-1. PNAS 106:2283–88
    [Google Scholar]
  63. 63.
    Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P et al. 2012. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLOS Biol. 10:e1001450
    [Google Scholar]
  64. 64.
    Kawai T, Akira S. 2006. Innate immune recognition of viral infection. Nat. Immunol. 7:131–37
    [Google Scholar]
  65. 65.
    Koessinger D, Novo D, Koessinger A, Zerbst D, Moore M et al. 2022. Glioblastoma exosomes influence glial cell hyaluronic acid deposition to promote invasiveness. bioRxiv 2022.02.11.480036. https://doi.org/10.1101/2022.02.11.480036
  66. 66.
    Kolodny GM, Culp LA, Rosenthal LJ. 1972. Secretion of RNA by normal and transformed cells. Exp. Cell. Res. 73:65–72
    [Google Scholar]
  67. 67.
    Koppers-Lalic D, Hackenberg M, Bijnsdorp IV, van Eijndhoven MAJ, Sadek P et al. 2014. Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes. Cell Rep. 8:1649–58
    [Google Scholar]
  68. 68.
    Kren BT, Wong PY-P, Sarver A, Zhang X, Zeng Y, Steer CJ. 2009. MicroRNAs identified in highly purified liver-derived mitochondria may play a role in apoptosis. RNA Biol. 6:65–72
    [Google Scholar]
  69. 69.
    Kumar M, Altan-Bonnet N 2021. Viral pores are everywhere. Mol. Cell 81:2061–63
    [Google Scholar]
  70. 70.
    Li K, Smagula CS, Parsons WJ, Richardson JA, Gonzalez M et al. 1994. Subcellular partitioning of MRP RNA assessed by ultrastructural and biochemical analysis. J. Cell Biol. 124:871–82
    [Google Scholar]
  71. 71.
    Li Y, Aggarwal MB, Nguyen K, Ke K, Spitale RC. 2017. Assaying RNA localization in situ with spatially restricted nucleobase oxidation. ACS Chem. Biol. 12:2709–14
    [Google Scholar]
  72. 72.
    Limpens RWAL, van der Schaar HM, Kumar D, Koster AJ, Snijder EJ et al. 2011. The transformation of enterovirus replication structures: a three-dimensional study of single- and double-membrane compartments. mBio 2:e00166–11
    [Google Scholar]
  73. 73.
    Lin A, Hu Q, Li C, Xing Z, Ma G et al. 2017. The LINK-A lncRNA interacts with PtdIns(3,4,5)P3 to hyperactivate AKT and confer resistance to AKT inhibitors. Nat. Cell Biol. 19:238–51
    [Google Scholar]
  74. 74.
    Lisenbee CS, Karnik SK, Trelease RN. 2003. Overexpression and mislocalization of a tail-anchored GFP redefines the identity of peroxisomal ER. Traffic 4:491–501
    [Google Scholar]
  75. 75.
    Liu X, Fu R, Pan Y, Meza-Sosa KF, Zhang Z, Lieberman J. 2018. PNPT1 release from mitochondria during apoptosis triggers decay of poly(A) RNAs. Cell 174:187–201.e12
    [Google Scholar]
  76. 76.
    Liu X-M, Ma L, Schekman R. 2021. Selective sorting of microRNAs into exosomes by phase-separated YBX1 condensates. eLife 10:e71982
    [Google Scholar]
  77. 77.
    Lu K-C, Zhang Y, Song E. 2019. Extracellular RNA: mechanisms of it's transporting into target cells. ExRNA 1:22
    [Google Scholar]
  78. 78.
    Lu L, Li J, Moussaoui M, Boix E. 2018. Immune modulation by human secreted RNases at the extracellular space. Front. Immunol. 9:1012
    [Google Scholar]
  79. 79.
    Mazeaud C, Anton A, Pahmeier F, Sow AA, Cerikan B et al. 2021. The biogenesis of dengue virus replication organelles requires the ATPase activity of valosin-containing protein. Viruses 13:2092
    [Google Scholar]
  80. 80.
    McEwan DL, Weisman AS, Hunter CP. 2012. Uptake of extracellular double-stranded RNA by SID-2. Mol. Cell 47:746–54
    [Google Scholar]
  81. 81.
    McKenzie AJ, Hoshino D, Hong NH, Cha DJ, Franklin JL et al. 2016. KRAS-MEK signaling controls Ago2 sorting into exosomes. Cell Rep. 15:978–87
    [Google Scholar]
  82. 82.
    Mechler B, Vassalli P. 1975. Membrane-bound ribosomes of myeloma cells. III. The role of the messenger RNA and the nascent polypeptide chain in the binding of ribosomes to membranes. J. Cell Biol. 67:25–37
    [Google Scholar]
  83. 83.
    Mercer TR, Neph S, Dinger ME, Crawford J, Smith MA et al. 2011. The human mitochondrial transcriptome. Cell 146:645–58
    [Google Scholar]
  84. 84.
    Moali C, Hulmes DJS. 2009. Extracellular and cell surface proteases in wound healing: new players are still emerging. Eur. J. Dermatol. 19:552–64
    [Google Scholar]
  85. 85.
    Morel L, Regan M, Higashimori H, Ng SK, Esau C et al. 2013. Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J. Biol. Chem. 288:7105–16
    [Google Scholar]
  86. 86.
    Murillo OD, Thistlethwaite W, Rozowsky J, Subramanian SL, Lucero R et al. 2019. exRNA Atlas analysis reveals distinct extracellular RNA cargo types and their carriers present across human biofluids. Cell 177:463–77.e15
    [Google Scholar]
  87. 87.
    Nechooshtan G, Yunusov D, Chang K, Gingeras TR. 2020. Processing by RNase 1 forms tRNA halves and distinct Y RNA fragments in the extracellular environment. Nucleic Acids Res. 48:8035–49
    [Google Scholar]
  88. 88.
    Neupert W, Herrmann JM. 2007. Translocation of proteins into mitochondria. Annu. Rev. Biochem. 76:723–49
    [Google Scholar]
  89. 89.
    Nguyen TA, Bieging-Rolett KT, Putoczki TL, Wicks IP, Attardi LD, Pang KC. 2019. SIDT2 RNA transporter promotes lung and gastrointestinal tumor development. iScience 20:14–24
    [Google Scholar]
  90. 90.
    Nguyen TA, Smith BRC, Elgass KD, Creed SJ, Cheung S et al. 2019. SIDT1 localizes to endolysosomes and mediates double-stranded RNA transport into the cytoplasm. J. Immunol. 202:3483–92
    [Google Scholar]
  91. 91.
    Nguyen TA, Smith BRC, Tate MD, Belz GT, Barrios MH et al. 2017. SIDT2 transports extracellular dsRNA into the cytoplasm for innate immune recognition. Immunity 47:498–509.e6
    [Google Scholar]
  92. 92.
    Noble JM, Roberts LM, Vidavsky N, Chiou AE, Fischbach C et al. 2020. Direct comparison of optical and electron microscopy methods for structural characterization of extracellular vesicles. J. Struct. Biol. 210:107474
    [Google Scholar]
  93. 93.
    Patton JG, Franklin JL, Weaver AM, Vickers K, Zhang B et al. 2015. Biogenesis, delivery, and function of extracellular RNA. J. Extracell. Vesicles 4:27494
    [Google Scholar]
  94. 94.
    Pegtel DM, Gould SJ. 2019. Exosomes. Annu. Rev. Biochem. 88:487–514
    [Google Scholar]
  95. 95.
    Pérez-Boza J, Boeckx A, Lion M, Dequiedt F, Struman I. 2020. hnRNPA2B1 inhibits the exosomal export of miR-503 in endothelial cells. Cell. Mol. Life Sci. 77:4413–28
    [Google Scholar]
  96. 96.
    Poltronieri P, Sun B, Mallardo M. 2015. RNA viruses: RNA roles in pathogenesis, coreplication and viral load. Curr. Genom. 16:327–35
    [Google Scholar]
  97. 97.
    Preissner KT, Fischer S, Deindl E. 2020. Extracellular RNA as a versatile DAMP and alarm signal that influences leukocyte recruitment in inflammation and infection. Front. Cell Dev. Biol. 8:619221
    [Google Scholar]
  98. 98.
    Rai A, Fang H, Claridge B, Simpson RJ, Greening DW. 2021. Proteomic dissection of large extracellular vesicle surfaceome unravels interactive surface platform. J. Extracell. Vesicles 10:e12164
    [Google Scholar]
  99. 99.
    Rainey RN, Glavin JD, Chen H-W, French SW, Teitell MA, Koehler CM. 2006. A new function in translocation for the mitochondrial i-AAA protease Yme1: import of polynucleotide phosphorylase into the intermembrane space. Mol. Cell. Biol. 26:8488–97
    [Google Scholar]
  100. 100.
    Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R et al. 2006. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20:847–56
    [Google Scholar]
  101. 101.
    Ricciardi S, Guarino AM, Giaquinto L, Polishchuk EV, Santoro M et al. 2022. The role of NSP6 in the biogenesis of the SARS-CoV-2 replication organelle. Nature 606:761–68
    [Google Scholar]
  102. 102.
    Rubio MAT, Rinehart JJ, Krett B, Duvezin-Caubet S, Reichert AS et al. 2008. Mammalian mitochondria have the innate ability to import tRNAs by a mechanism distinct from protein import. PNAS 105:9186–91
    [Google Scholar]
  103. 103.
    Saint-Georges Y, Garcia M, Delaveau T, Jourdren L, Le Crom S et al. 2008. Yeast mitochondrial biogenesis: a role for the PUF RNA-binding protein Puf3p in mRNA localization. PLOS ONE 3:e2293
    [Google Scholar]
  104. 104.
    Salinas T, Duchêne A-M, Delage L, Nilsson S, Glaser E et al. 2006. The voltage-dependent anion channel, a major component of the tRNA import machinery in plant mitochondria. PNAS 103:18362–67
    [Google Scholar]
  105. 105.
    Salinas T, El Farouk-Ameqrane S, Ubrig E, Sauter C, Duchêne A-M, Maréchal-Drouard L 2014. Molecular basis for the differential interaction of plant mitochondrial VDAC proteins with tRNAs. Nucleic Acids Res. 42:9937–48
    [Google Scholar]
  106. 106.
    Sharma U, Conine CC, Shea JM, Boskovic A, Derr AG et al. 2016. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351:391–96
    [Google Scholar]
  107. 107.
    Shih JD, Fitzgerald MC, Sutherlin M, Hunter CP. 2009. The SID-1 double-stranded RNA transporter is not selective for dsRNA length. RNA 15:384–90
    [Google Scholar]
  108. 108.
    Shih JD, Hunter CP. 2011. SID-1 is a dsRNA-selective dsRNA-gated channel. RNA 17:1057–65
    [Google Scholar]
  109. 109.
    Siwecka N, Rozpędek-Kamińska W, Wawrzynkiewicz A, Pytel D, Diehl JA, Majsterek I. 2021. The structure, activation and signaling of IRE1 and its role in determining cell fate. Biomedicines 9:156
    [Google Scholar]
  110. 110.
    Snijder EJ, Decroly E, Ziebuhr J. 2016. The nonstructural proteins directing coronavirus RNA synthesis and processing. Adv. Virus Res. 96:59–126
    [Google Scholar]
  111. 111.
    Squadrito ML, Baer C, Burdet F, Maderna C, Gilfillan GD et al. 2014. Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells. Cell Rep. 8:1432–46
    [Google Scholar]
  112. 112.
    Takahashi M, Contu VR, Kabuta C, Hase K, Fujiwara Y et al. 2017. SIDT2 mediates gymnosis, the uptake of naked single-stranded oligonucleotides into living cells. RNA Biol. 14:1534–43
    [Google Scholar]
  113. 113.
    Takahashi M, Seki M, Nashimoto M, Kabuta T. 2021. Perturbing the normal level of SIDT1 suppresses the naked ASO effect. J. Nucleic Acids 2021:2458470
    [Google Scholar]
  114. 114.
    Tarassov I, Entelis N, Martin RP. 1995. An intact protein translocating machinery is required for mitochondrial import of a yeast cytoplasmic tRNA. J. Mol. Biol. 245:315–23
    [Google Scholar]
  115. 115.
    Tatematsu M, Funami K, Seya T, Matsumoto M. 2018. Extracellular RNA sensing by pattern recognition receptors. J. Innate Immun. 10:398–406
    [Google Scholar]
  116. 116.
    Temoche-Diaz MM, Shurtleff MJ, Nottingham RM, Yao J, Fadadu RP et al. 2019. Distinct mechanisms of microRNA sorting into cancer cell-derived extracellular vesicle subtypes. eLife 8:e47544
    [Google Scholar]
  117. 117.
    Thomas SP, Hoang TT, Ressler VT, Raines RT. 2018. Human angiogenin is a potent cytotoxin in the absence of ribonuclease inhibitor. RNA 24:1018–27
    [Google Scholar]
  118. 118.
    Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M et al. 2017. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature 542:450–55
    [Google Scholar]
  119. 119.
    Timmons L, Fire A. 1998. Specific interference by ingested dsRNA. Nature 395:854
    [Google Scholar]
  120. 120.
    Tosar JP, Cayota A, Eitan E, Halushka MK, Witwer KW. 2017. Ribonucleic artefacts: are some extracellular RNA discoveries driven by cell culture medium components?. J. Extracell. Vesicles 6:1272832
    [Google Scholar]
  121. 121.
    Tosar JP, Gámbaro F, Darré L, Pantano S, Westhof E, Cayota A. 2018. Dimerization confers increased stability to nucleases in 5′ halves from glycine and glutamic acid tRNAs. Nucleic Acids Res. 46:9081–93
    [Google Scholar]
  122. 122.
    Tosar JP, Gámbaro F, Sanguinetti J, Bonilla B, Witwer KW, Cayota A. 2015. Assessment of small RNA sorting into different extracellular fractions revealed by high-throughput sequencing of breast cell lines. Nucleic Acids Res. 43:5601–16
    [Google Scholar]
  123. 123.
    Tosar JP, Segovia M, Castellano M, Gámbaro F, Akiyama Y et al. 2020. Fragmentation of extracellular ribosomes and tRNAs shapes the extracellular RNAome. Nucleic Acids Res. 48:12874–88
    [Google Scholar]
  124. 124.
    Tosar JP, Witwer K, Cayota A. 2021. Revisiting extracellular RNA release, processing, and function. Trends Biochem. Sci. 46:438–45
    [Google Scholar]
  125. 125.
    Tsang SY, Moore JC, Huizen RV, Chan CWY, Li RA. 2007. Ectopic expression of systemic RNA interference defective protein in embryonic stem cells. Biochem. Biophys. Res. Commun. 357:480–86
    [Google Scholar]
  126. 126.
    Turchinovich A, Weiz L, Langheinz A, Burwinkel B. 2011. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 39:7223–33
    [Google Scholar]
  127. 127.
    Unchwaniwala N, Zhan H, Pennington J, Horswill M, den Boon JA, Ahlquist P. 2020. Subdomain cryo-EM structure of nodaviral replication protein A crown complex provides mechanistic insights into RNA genome replication. PNAS 117:18680–91
    [Google Scholar]
  128. 128.
    van der Grein SG, Nolte-’t Hoen ENM. 2014.. “ Small talk” in the innate immune system via RNA-containing extracellular vesicles. Front. Immunol. 5:542
    [Google Scholar]
  129. 129.
    Veziroglu EM, Mias GI. 2020. Characterizing extracellular vesicles and their diverse RNA contents. Front. Genet. 11:700
    [Google Scholar]
  130. 130.
    Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. 2011. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13:423–33
    [Google Scholar]
  131. 131.
    Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Cabo F, Pérez-Hernández D, Vázquez J et al. 2013. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4:2980
    [Google Scholar]
  132. 132.
    Walter P, Blobel G. 1980. Purification of a membrane-associated protein complex required for protein translocation across the endoplasmic reticulum. PNAS 77:7112–16
    [Google Scholar]
  133. 133.
    Walter P, Blobel G. 1981. Translocation of proteins across the endoplasmic reticulum. II. Signal recognition protein (SRP) mediates the selective binding to microsomal membranes of in-vitro-assembled polysomes synthesizing secretory protein. J. Cell Biol. 91:551–56
    [Google Scholar]
  134. 134.
    Walter P, Blobel G. 1982. Signal recognition particle contains a 7S RNA essential for protein translocation across the endoplasmic reticulum. Nature 299:691–98
    [Google Scholar]
  135. 135.
    Walter P, Ron D 2011. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334:1081–86
    [Google Scholar]
  136. 136.
    Wang G, Chen H-W, Oktay Y, Zhang J, Allen EL et al. 2010. PNPASE regulates RNA import into mitochondria. Cell 142:456–67
    [Google Scholar]
  137. 137.
    Wang J, Silva M, Haas LA, Morsci NS, Nguyen KCQ et al. 2014. C. elegans ciliated sensory neurons release extracellular vesicles that function in animal communication. Curr. Biol. 24:519–25
    [Google Scholar]
  138. 138.
    Wang K, Zhang S, Weber J, Baxter D, Galas DJ. 2010. Export of microRNAs and microRNA-protective protein by mammalian cells. Nucleic Acids Res. 38:7248–59
    [Google Scholar]
  139. 139.
    Welsch S, Miller S, Romero-Brey I, Merz A, Bleck CKE et al. 2009. Composition and three-dimensional architecture of the dengue virus replication and assembly sites. Cell Host Microbe 5:365–75
    [Google Scholar]
  140. 140.
    Wiedemann N, Pfanner N. 2017. Mitochondrial machineries for protein import and assembly. Annu. Rev. Biochem. 86:685–714
    [Google Scholar]
  141. 141.
    Winston WM, Molodowitch C, Hunter CP. 2002. Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science 295:2456–59
    [Google Scholar]
  142. 142.
    Winston WM, Sutherlin M, Wright AJ, Feinberg EH, Hunter CP. 2007. Caenorhabditis elegans SID-2 is required for environmental RNA interference. PNAS 104:10565–70
    [Google Scholar]
  143. 143.
    Wolff G, Limpens RWAL, Zevenhoven-Dobbe JC, Laugks U, Zheng S et al. 2020. A molecular pore spans the double membrane of the coronavirus replication organelle. Science 369:1395–98
    [Google Scholar]
  144. 144.
    Wolff G, Melia CE, Snijder EJ, Bárcena M. 2020. Double-membrane vesicles as platforms for viral replication. Trends Microbiol. 28:1022–33
    [Google Scholar]
  145. 145.
    Wolfrum C, Shi S, Jayaprakash KN, Jayaraman M, Wang G et al. 2007. Mechanisms and optimization of in vivo delivery of lipophilic siRNAs. Nat. Biotechnol. 25:1149–57
    [Google Scholar]
  146. 146.
    Wu E, Guo X, Teng X, Zhang R, Li F et al. 2021. Discovery of plasma membrane-associated RNAs through APEX-seq. Cell Biochem. Biophys. 79:905–17
    [Google Scholar]
  147. 147.
    Yehudai-Resheff S, Hirsh M, Schuster G. 2001. Polynucleotide phosphorylase functions as both an exonuclease and a poly(A) polymerase in spinach chloroplasts. Mol. Cell. Biol. 21:5408–16
    [Google Scholar]
  148. 148.
    Yoshida H, Haze K, Yanagi H, Yura T, Mori K. 1998. Identification of the cis-acting endoplasmic reticulum stress response element responsible for transcriptional induction of mammalian glucose-regulated proteins: involvement of basic leucine zipper transcription factors. J. Biol. Chem. 273:33741–49
    [Google Scholar]
  149. 149.
    Yoshionari S, Koike T, Yokogawa T, Nishikawa K, Ueda T et al. 1994. Existence of nuclear-encoded 5S-rRNA in bovine mitochondria. FEBS Lett. 338:137–42
    [Google Scholar]
  150. 150.
    Zhang J, Li S, Li L, Li M, Guo C et al. 2015. Exosome and exosomal microRNA: trafficking, sorting, and function. Genom. Proteom. Bioinform. 13:17–24
    [Google Scholar]
  151. 151.
    Zhang K, Law Y-S, Law MCY, Tan YB, Wirawan M, Luo D. 2021. Structural insights into viral RNA capping and plasma membrane targeting by Chikungunya virus nonstructural protein 1. Cell Host Microbe 29:757–64.e3
    [Google Scholar]
  152. 152.
    Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q et al. 2015. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527:100–104
    [Google Scholar]
  153. 153.
    Zhang Y, Zhang Y, Shi J, Zhang H, Cao Z et al. 2014. Identification and characterization of an ancient class of small RNAs enriched in serum associating with active infection. J. Mol. Cell Biol. 6:172–74
    [Google Scholar]
  154. 154.
    Zhao L, Ning Q, Zheng G, Luo J, Dong D. 2022. exRNAdisease: an extracellular RNA transcriptome atlas in human diseases. Gene 836:146662
    [Google Scholar]
  155. 155.
    Zhou G, Chen X. 2019. Emerging role of extracellular microRNAs and lncRNAs. ExRNA 1:10
    [Google Scholar]
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