Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Membrane linked RNA glycosylation as new trend to envision epi-transcriptome epoch

Cancer Gene Therapy volume 30, pages 641–646 (2023)Cite this article

Subjects

Abstract

RNAs play several prominent roles in the cellular environment ranging from structural, messengers, translators, and effector molecules. RNA molecules while performing these roles are associated with several chemical modifications occurring post-transcriptionally, responsible for these supporting vital functions. The recent documentation of surface RNA modification with sialic acid residues has sparked advancement to the framework of RNA modifications. Glycan modification of surface RNA which was previously known to modify only proteins and lipids has opened new vistas to explore how these surface RNA modifications affect the cellular responses and phenotype. This paradigm shift in RNA biology with a vision of “glycans being all over the cells” has posed the field with a repertoire of questions and has given headway to the RNA world hypothesis. The review provides a comprehensive overview of glycoRNA discovery with a conceptual understanding of its previous underlying discoveries and their biological consequences with possible insights into the dynamic influence of this modification on their molecular versatility deciding cancer-immunology fate with potential implications of these glycosylation in cellular interaction, signaling, immune regulation, cancer evasion and proliferation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Surface localization of glycoRNA and its interactions.
Fig. 2: The milestone in discovery of glycoRNAs on the cell surface.
Fig. 3: The falling limelight on future possibility of events resulting from the glycoRNA discovery.

Similar content being viewed by others

References

  1. Murn J, Shi Y. The winding path of protein methylation research: milestones and new frontiers. Nat Rev Mol Cell Biol. 2017;18:517–27.

    Article  CAS  PubMed  Google Scholar 

  2. Narita T, Weinert BT, Choudhary C. Author Correction: Functions and mechanisms of non-histone protein acetylation. Nat Rev Mol Cell Biol. 2019;20:508.

    Article  CAS  PubMed  Google Scholar 

  3. Cohen P. The origins of protein phosphorylation. Nat Cell Biol. 2002;4:E127–30.

    Article  CAS  PubMed  Google Scholar 

  4. Swatek KN, Komander D. Ubiquitin modifications. Cell Res. 2016;26:399–422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Spicer CD, Davis BG. Selective chemical protein modification. Nat Commun. 2014;5:4740.

    Article  CAS  PubMed  Google Scholar 

  6. Schubeler D. Function and information content of DNA methylation. Nature. 2015;517:321–6.

    Article  CAS  PubMed  Google Scholar 

  7. Wyatt GR. Occurrence of 5-methylcytosine in nucleic acids. Nature. 1950;166:237–8.

    Article  CAS  PubMed  Google Scholar 

  8. Adams JM, Cory S. Modified nucleosides and bizarre 5’-termini in mouse myeloma mRNA. Nature. 1975;255:28–33.

    Article  CAS  PubMed  Google Scholar 

  9. Perry RP, Kelley DE, Friderici K, Rottman F. The methylated constituents of L cell messenger RNA: evidence for an unusual cluster at the 5’ terminus. Cell. 1975;4:387–94.

    Article  CAS  PubMed  Google Scholar 

  10. Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA modifications in gene expression regulation. Cell. 2017;169:1187–1200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Norbury CJ. Cytoplasmic RNA: a case of the tail wagging the dog. Nat Rev Mol Cell Biol. 2013;14:643–53.

    Article  CAS  PubMed  Google Scholar 

  12. Chang H, Lim J, Ha M, Kim VN. TAIL-seq: genome-wide determination of poly(A) tail length and 3’ end modifications. Mol Cell. 2014;53:1044–52.

    Article  CAS  PubMed  Google Scholar 

  13. Sierant M, Leszczynska G, Sadowska K, Komar P, Radzikowska-Cieciura E, Sochacka E, et al. Escherichia coli tRNA 2-selenouridine synthase (SelU) converts S2U-RNA to Se2U-RNA via S-geranylated-intermediate. FEBS Lett. 2018;592:2248–58.

    Article  CAS  PubMed  Google Scholar 

  14. Kasai H, Nakanishi K, Macfarlane RD, Torgerson DF, Ohashi Z, McCloskey JA, et al. Letter: The structure of Q* nucleoside isolated from rabbit liver transfer ribonucleic acid. J Am Chem Soc. 1976;98:5044–6.

    Article  CAS  PubMed  Google Scholar 

  15. Sinha KM, Gu J, Chen Y, Reddy R. Adenylation of small RNAs in human cells. Development of a cell-free system for accurate adenylation on the 3’-end of human signal recognition particle RNA. J Biol Chem. 1998;273:6853–9.

    Article  CAS  PubMed  Google Scholar 

  16. Mullen TE, Marzluff WF. Degradation of histone mRNA requires oligouridylation followed by decapping and simultaneous degradation of the mRNA both 5’ to 3’ and 3’ to 5’. Genes Dev. 2008;22:50–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rissland OS, Norbury CJ. Decapping is preceded by 3’ uridylation in a novel pathway of bulk mRNA turnover. Nat Struct Mol Biol. 2009;16:616–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yoluc Y, Ammann G, Barraud P, Jora M, Limbach PA, Motorin Y, et al. Instrumental analysis of RNA modifications. Crit Rev Biochem Mol Biol. 2021;56:178–204.

    Article  CAS  PubMed  Google Scholar 

  19. Luo X, Li H, Liang J, Zhao Q, Xie Y, Ren J, et al. RMVar: an updated database of functional variants involved in RNA modifications. Nucleic Acids Res. 2021;49:D1405–D1412.

    Article  CAS  PubMed  Google Scholar 

  20. Boccaletto P, Machnicka MA, Purta E, Piatkowski P, Baginski B, Wirecki TK, et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res. 2018;46:D303–D307.

    Article  CAS  PubMed  Google Scholar 

  21. Rottman F, Shatkin AJ, Perry RP. Sequences containing methylated nucleotides at the 5’ termini of messenger RNAs: possible implications for processing. Cell. 1974;3:197–9.

    Article  CAS  PubMed  Google Scholar 

  22. Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015;518:560–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Alarcon CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events. Cell. 2015;162:1299–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kawai G, Yamamoto Y, Kamimura T, Masegi T, Sekine M, Hata T, et al. Conformational rigidity of specific pyrimidine residues in tRNA arises from posttranscriptional modifications that enhance steric interaction between the base and the 2’-hydroxyl group. Biochemistry. 1992;31:1040–6.

    Article  CAS  PubMed  Google Scholar 

  25. Sheng J, Zhang W, Hassan AE, Gan J, Soares AS, Geng S, et al. Hydrogen bond formation between the naturally modified nucleobase and phosphate backbone. Nucleic Acids Res. 2012;40:8111–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Taoka M, Nobe Y, Yamaki Y, Sato K, Ishikawa H, Izumikawa K, et al. Landscape of the complete RNA chemical modifications in the human 80S ribosome. Nucleic Acids Res. 2018;46:9289–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kim YK, Heo I, Kim VN. Modifications of small RNAs and their associated proteins. Cell. 2010;143:703–9.

    Article  CAS  PubMed  Google Scholar 

  28. Karijolich J, Yu YT. Spliceosomal snRNA modifications and their function. RNA Biol. 2010;7:192–204.

    Article  CAS  PubMed  Google Scholar 

  29. Trixl L, Lusser A. The dynamic RNA modification 5-methylcytosine and its emerging role as an epitranscriptomic mark. Wiley Interdiscip Rev RNA. 2019;10:e1510.

    Article  PubMed  Google Scholar 

  30. Keffer-Wilkes LC, Soon EF, Kothe U. The methyltransferase TrmA facilitates tRNA folding through interaction with its RNA-binding domain. Nucleic Acids Res. 2020;48:7981–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Di Timoteo G, Dattilo D, Centron-Broco A, Colantoni A, Guarnacci M, Rossi F, et al. Modulation of circRNA Metabolism by m(6)A Modification. Cell Rep. 2020;31:107641.

    Article  PubMed  Google Scholar 

  32. Yang Y, Fan X, Mao M, Song X, Wu P, Zhang Y, et al. Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Res. 2017;27:626–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen YG, Chen R, Ahmad S, Verma R, Kasturi SP, Amaya L, et al. N6-methyladenosine modification controls circular RNA immunity. Mol Cell. 2019;76:96–109 e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Okada N, Nishimura S. Enzymatic synthesis of Q nucleoside containing mannose in the anticodon of tRNA: isolation of a novel mannosyltransferase from a cell-free extract of rat liver. Nucleic Acids Res. 1977;4:2931–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Flynn RA, Pedram K, Malaker SA, Batista PJ, Smith BAH, Johnson AG, et al. Small RNAs are modified with N-glycans and displayed on the surface of living cells. Cell. 2021;184:3109–24 e22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tarentino AL, Plummer TH Jr. Enzymatic deglycosylation of asparagine-linked glycans: purification, properties, and specificity of oligosaccharide-cleaving enzymes from Flavobacterium meningosepticum. Methods Enzymol. 1994;230:44–57.

    Article  CAS  PubMed  Google Scholar 

  37. Duan S, Paulson JC. Siglecs as immune cell checkpoints in disease. Annu Rev Immunol. 2020;38:365–95.

    Article  CAS  PubMed  Google Scholar 

  38. Macauley MS, Crocker PR, Paulson JC. Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol. 2014;14:653–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chang YC, Nizet V. Siglecs at the host-pathogen interface. Adv Exp Med Biol. 2020;1204:197–214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fraschilla I, Pillai S. Viewing Siglecs through the lens of tumor immunology. Immunol Rev. 2017;276:178–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Stanczak MA, Siddiqui SS, Trefny MP, Thommen DS, Boligan KF, von Gunten S, et al. Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells. J Clin Investig. 2018;128:4912–23.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Flores R, Zhang P, Wu W, Wang X, Ye P, Zheng P, et al. Siglec genes confer resistance to systemic lupus erythematosus in humans and mice. Cell Mol Immunol. 2019;16:154–64.

    Article  CAS  PubMed  Google Scholar 

  43. Angata T. Associations of genetic polymorphisms of Siglecs with human diseases. Glycobiology. 2014;24:785–93.

    Article  CAS  PubMed  Google Scholar 

  44. Wang Y, Neumann H. Alleviation of neurotoxicity by microglial human Siglec-11. J Neurosci. 2010;30:3482–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tsai CM, Riestra AM, Ali SR, Fong JJ, Liu JZ, Hughes G, et al. Siglec-14 enhances NLRP3-inflammasome activation in macrophages. J innate Immun. 2020;12:333–43.

    Article  CAS  PubMed  Google Scholar 

  46. Liu YC, Yu MM, Chai YF, Shou ST. Sialic acids in the immune response during sepsis. Front Immunol. 2017;8:1601.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Huang N, Fan X, Zaleta-Rivera K, Nguyen TC, Zhou J, Luo Y, et al. Natural display of nuclear-encoded RNA on the cell surface and its impact on cell interaction. Genome Biol. 2020;21:225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Janas T, Yarus M. Visualization of membrane RNAs. RNA. 2003;9:1353–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Morozkin ES, Laktionov PP, Rykova EY, Vlassov VV. Extracellular nucleic acids in cultures of long-term cultivated eukaryotic cells. Ann N. Y Acad Sci. 2004;1022:244–9.

    Article  CAS  PubMed  Google Scholar 

  50. Block KF, Puerta-Fernandez E, Wallace JG, Breaker RR. Association of OLE RNA with bacterial membranes via an RNA-protein interaction. Mol Microbiol. 2011;79:21–34.

    Article  CAS  PubMed  Google Scholar 

  51. Janas T, Janas T, Yarus M. Human tRNA(Sec) associates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers. RNA. 2012;18:2260–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lin A, Hu Q, Li C, Xing Z, Ma G, Wang C, et al. The LINK-A lncRNA interacts with PtdIns(3,4,5)P3 to hyperactivate AKT and confer resistance to AKT inhibitors. Nat Cell Biol. 2017;19:238–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hirschberg CB, Snider MD. Topography of glycosylation in the rough endoplasmic reticulum and Golgi apparatus. Annu Rev Biochem. 1987;56:63–87.

    Article  CAS  PubMed  Google Scholar 

  54. Aebi M. N-linked protein glycosylation in the ER. Bioch et Biophys Acta. 2013;1833:2430–7.

    Article  CAS  Google Scholar 

  55. Hirschberg CB, Robbins PW, Abeijon C. Transporters of nucleotide sugars, ATP, and nucleotide sulfate in the endoplasmic reticulum and Golgi apparatus. Annu Rev Biochem. 1998;67:49–69.

    Article  CAS  PubMed  Google Scholar 

  56. Gandini R, Reichenbach T, Tan TC, Divne C. Structural basis for dolichylphosphate mannose biosynthesis. Nat Commun. 2017;8:120.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Moremen KW, Tiemeyer M, Nairn AV. Vertebrate protein glycosylation: diversity, synthesis and function. Nat Rev Mol Cell Biol. 2012;13:448–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Helm M. Post-transcriptional nucleotide modification and alternative folding of RNA. Nucleic Acids Res. 2006;34:721–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kruger K, Grabowski PJ, Zaug AJ, Sands J, Gottschling DE, Cech TR. Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena. Cell. 1982;31:147–57.

    Article  CAS  PubMed  Google Scholar 

  60. Guerrier-Takada C, Gardiner K, Marsh T, Pace N, Altman S. The RNA moiety of ribonuclease P is the catalytic subunit of the enzyme. Cell. 1983;35:849–57.

    Article  CAS  PubMed  Google Scholar 

  61. Chan CT, Pang YL, Deng W, Babu IR, Dyavaiah M, Begley TJ, et al. Reprogramming of tRNA modifications controls the oxidative stress response by codon-biased translation of proteins. Nat Commun. 2012;3:937.

    Article  PubMed  Google Scholar 

  62. Begley U, Dyavaiah M, Patil A, Rooney JP, DiRenzo D, Young CM, et al. Trm9-catalyzed tRNA modifications link translation to the DNA damage response. Mol Cell. 2007;28:860–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Endres L, Dedon PC, Begley TJ. Codon-biased translation can be regulated by wobble-base tRNA modification systems during cellular stress responses. RNA Biol. 2015;12:603–14.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Nachtergaele S, Krishnan Y. New Vistas for Cell-Surface GlycoRNAs. N. Engl J Med. 2021;385:658–60.

    Article  PubMed  Google Scholar 

  65. Silsirivanit A. Glycosylation markers in cancer. Adv Clin Chem. 2019;89:189–213.

    Article  CAS  PubMed  Google Scholar 

  66. Narayanan S. Sialic acid as a tumor marker. Ann Clin Lab Sci. 1994;24:376–84.

    CAS  PubMed  Google Scholar 

  67. Boligan KF, Mesa C, Fernandez LE, von Gunten S. Cancer intelligence acquired (CIA): tumor glycosylation and sialylation codes dismantling antitumor defense. Cell Mol Life Sci. 2015;72:1231–48.

    Article  CAS  PubMed  Google Scholar 

  68. Pinho SS, Reis CA. Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer. 2015;15:540–55.

    Article  CAS  PubMed  Google Scholar 

  69. Tkach M, Thery C. Communication by extracellular vesicles: where we are and where we need to go. Cell. 2016;164:1226–32.

    Article  CAS  PubMed  Google Scholar 

  70. Robertson JD. Membrane structure. J Cell Biol. 1981;91:189s–204s.

    Article  CAS  PubMed  Google Scholar 

  71. Singer SJ, Nicolson GL. The fluid mosaic model of the structure of cell membranes. Science. 1972;175:720–31.

    Article  CAS  PubMed  Google Scholar 

  72. Lombard J. Once upon a time the cell membranes: 175 years of cell boundary research. Biol Direct. 2014;9:32.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors also acknowledge the financial support from Indian government. WT was supported by a fellowship from the DST-INSPIRE, Government of India. VP was supported by a fellowship from Department of Biotechnology, Government of India.

Author information

Author notes

  1. These authors contributed equally: Witty Tyagi, Vivek Pandey.

Authors and Affiliations

  1. Molecular Oncology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India

    Witty Tyagi

  2. Faculty of Life Science and Biotechnology, South Asian University, Akbar Bhawan, Chanakyapuri, New Delhi, India

    Vivek Pandey & Yuba Raj Pokharel

Authors
  1. Witty Tyagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vivek Pandey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuba Raj Pokharel
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WT and VP designed and conceived the study. WT, VP, wrote the initial manuscript WT designed the graphical figures. WT, VP, YRP discussed content, reviewed and edited the manuscript.

Corresponding author

Correspondence to Yuba Raj Pokharel.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tyagi, W., Pandey, V. & Pokharel, Y.R. Membrane linked RNA glycosylation as new trend to envision epi-transcriptome epoch. Cancer Gene Ther 30, 641–646 (2023). https://doi.org/10.1038/s41417-022-00430-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-022-00430-z

This article is cited by

Search

Advanced search

Quick links