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:

Translational control of immune responses: from transcripts to translatomes

Nature Immunology volume 15, pages 503–511 (2014)Cite this article

Subjects

Abstract

Selective translational control of gene expression is emerging as a principal mechanism for the regulation of protein abundance that determines a variety of functions in both the adaptive immune system and the innate immune system. The translation-initiation factor eIF4E acts as a node for such regulation, but non-eIF4E mechanisms are also prevalent. Studies of 'translatomes' (genome-wide pools of translated mRNA) have facilitated mechanistic discoveries by identifying key regulatory components, including transcription factors, that are under translational control. Here we review the current knowledge on mechanisms that regulate translation and thereby modulate immunological function. We further describe approaches for measuring and analyzing translatomes and how such powerful tools can facilitate future insights on the role of translational control in the immune system.

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

Figure 1: The PTO model.
Figure 2: eIF4E is a node for regulation of immune functions via translational control.
Figure 3: Polysome- and ribosome-profiling techniques are used to measure the translatome.

Similar content being viewed by others

References

  1. Bava, F.A. et al. CPEB1 coordinates alternative 3′-UTR formation with translational regulation. Nature 495, 121–125 (2013).

    Article  CAS  PubMed  Google Scholar 

  2. Rousseau, D., Kaspar, R., Rosenwald, I., Gehrke, L. & Sonenberg, N. Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E. Proc. Natl. Acad. Sci. USA 93, 1065–1070 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lindstein, T., June, C.H., Ledbetter, J.A., Stella, G. & Thompson, C.B. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science 244, 339–343 (1989).

    Article  CAS  PubMed  Google Scholar 

  4. Schena, M. et al. Parallel human genome analysis: microarray-based expression monitoring of 1000 genes. Proc. Natl. Acad. Sci. USA 93, 10614–10619 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Schena, M., Shalon, D., Davis, R.W. & Brown, P.O. Quantitative monitoring of gene expression patterns with a complementary DNA microarray. Science 270, 467–470 (1995).

    Article  CAS  PubMed  Google Scholar 

  6. Lockhart, D.J. et al. Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat. Biotechnol. 14, 1675–1680 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Larsson, O., Tian, B. & Sonenberg, N. Toward a genome-wide landscape of translational control. Cold Spring Harb. Perspect. Biol. 5, a012302 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Vogel, C. & Marcotte, E.M. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat. Rev. Genet. 13, 227–232 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Schwanhäusser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).

    Article  PubMed  CAS  Google Scholar 

  10. Kristensen, A.R., Gsponer, J. & Foster, L.J. Protein synthesis rate is the predominant regulator of protein expression during differentiation. Mol. Syst. Biol. 10.1038/msb.2013.47 (17 September 2013).This study identifies translational control as the principal mechanism among post-transcriptional and post-translational mechanisms for the dynamic regulation of gene expression.

  11. Spirin, A.S. The second Sir Hans Krebs lecture. Informosomes. Eur. J. Biochem. 10, 20–35 (1969).

    Article  CAS  PubMed  Google Scholar 

  12. Keene, J.D. & Tenenbaum, S.A. Eukaryotic mRNPs may represent posttranscriptional operons. Mol. Cell 9, 1161–1167 (2002).This study introduces the present conceptual model for the regulation of gene expression at the post-transcriptional level.

    Article  CAS  PubMed  Google Scholar 

  13. Candeias, M.M. et al. P53 mRNA controls p53 activity by managing Mdm2 functions. Nat. Cell Biol. 10, 1098–1105 (2008).

    Article  CAS  PubMed  Google Scholar 

  14. Hershey, J.W., Sonenberg, N. & Mathews, M.B. Principles of translational control: an overview. Cold Spring Harb. Perspect. Biol. 4, a011528 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Shalgi, R. et al. Widespread regulation of translation by elongation pausing in heat shock. Mol. Cell 49, 439–452 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liu, B., Han, Y. & Qian, S.B. Cotranslational response to proteotoxic stress by elongation pausing of ribosomes. Mol. Cell 49, 453–463 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gerashchenko, M.V., Lobanov, A.V. & Gladyshev, V.N. Genome-wide ribosome profiling reveals complex translational regulation in response to oxidative stress. Proc. Natl. Acad. Sci. USA 109, 17394–17399 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Leprivier, G. et al. The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation. Cell 153, 1064–1079 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sonenberg, N. & Hinnebusch, A.G. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. Cell 136, 731–745 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jackson, R.J., Hellen, C.U. & Pestova, T.V. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat. Rev. Mol. Cell Biol. 11, 113–127 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Baltz, A.G. et al. The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Mol. Cell 46, 674–690 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Castello, A. et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149, 1393–1406 (2012).

    Article  CAS  PubMed  Google Scholar 

  23. Sabatini, D.M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S.H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35–43 (1994).

    Article  CAS  PubMed  Google Scholar 

  24. Brown, E.J. et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756–758 (1994).

    Article  CAS  PubMed  Google Scholar 

  25. Gwinn, D.M. et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol. Cell 30, 214–226 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Inoki, K., Zhu, T. & Guan, K.L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577–590 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Corradetti, M.N., Inoki, K., Bardeesy, N., DePinho, R.A. & Guan, K.L. Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev. 18, 1533–1538 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shaw, R.J. et al. The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 6, 91–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  29. Hara, K. et al. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J. Biol. Chem. 273, 14484–14494 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Wang, X., Campbell, L.E., Miller, C.M. & Proud, C.G. Amino acid availability regulates p70 S6 kinase and multiple translation factors. Biochem. J. 334, 261–267 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. DeYoung, M.P., Horak, P., Sofer, A., Sgroi, D. & Ellisen, L.W. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14–3-3 shuttling. Genes Dev. 22, 239–251 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Brugarolas, J. et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 18, 2893–2904 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Laplante, M. & Sabatini, D.M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kim, D.H. et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110, 163–175 (2002).

    Article  CAS  PubMed  Google Scholar 

  35. Hara, K. et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110, 177–189 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6, 1122–1128 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Sarbassov, D.D. et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Sarbassov, D.D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Heitman, J., Movva, N.R. & Hall, M.N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253, 905–909 (1991).

    Article  CAS  PubMed  Google Scholar 

  40. Gingras, A.C. et al. Regulation of 4E–BP1 phosphorylation: a novel two-step mechanism. Genes Dev. 13, 1422–1437 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Brunn, G.J. et al. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J. 15, 5256–5267 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Burnett, P.E., Barrow, R.K., Cohen, N.A., Snyder, S.H. & Sabatini, D.M. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E–BP1. Proc. Natl. Acad. Sci. USA 95, 1432–1437 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hara, K. et al. Regulation of eIF-4E BP1 phosphorylation by mTOR. J. Biol. Chem. 272, 26457–26463 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Wullschleger, S., Loewith, R. & Hall, M.N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Dorrello, N.V. et al. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314, 467–471 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Raught, B. et al. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 23, 1761–1769 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Pause, A. et al. Insulin-dependent stimulation of protein synthesis by phosphorylation of a regulator of 5′-cap function. Nature 371, 762–767 (1994).

    Article  CAS  PubMed  Google Scholar 

  48. Roux, P.P. & Topisirovic, I. Regulation of mRNA translation by signaling pathways. Cold Spring Harb. Perspect. Biol. 4, a012252 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Gingras, A.C. et al. Hierarchical phosphorylation of the translation inhibitor 4E–BP1. Genes Dev. 15, 2852–2864 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zimmer, S.G., DeBenedetti, A. & Graff, J.R. Translational control of malignancy: the mRNA cap-binding protein, eIF-4E, as a central regulator of tumor formation, growth, invasion and metastasis. Anticancer Res. 20, 3A, 1343–1351 (2000).

    Google Scholar 

  51. Colina, R. et al. Translational control of the innate immune response through IRF-7. Nature 452, 323–328 (2008).This study identifies mTORC1–4E-BP–dependent translational control of IRF7, which affects the production of type 1 interferon and susceptibility to infection with vesicular stomatitis virus.

    Article  CAS  PubMed  Google Scholar 

  52. Larsson, O. et al. Apoptosis resistance downstream of eIF4E: posttranscriptional activation of an anti-apoptotic transcript carrying a consensus hairpin structure. Nucleic Acids Res. 34, 4375–4386 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Hsieh, A.C. et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 485, 55–61 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Thoreen, C.C. et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature 485, 109–113 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bilanges, B. et al. Tuberous sclerosis complex proteins 1 and 2 control serum-dependent translation in a TOP-dependent and -independent manner. Mol. Cell. Biol. 27, 5746–5764 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Patursky-Polischuk, I. et al. The TSC-mTOR pathway mediates translational activation of TOP mRNAs by insulin largely in a raptor- or rictor-independent manner. Mol. Cell. Biol. 29, 640–649 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Avni, D., Shama, S., Loreni, F. & Meyuhas, O. Vertebrate mRNAs with a 5′-terminal pyrimidine tract are candidates for translational repression in quiescent cells: characterization of the translational cis-regulatory element. Mol. Cell. Biol. 14, 3822–3833 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Miloslavski, R. et al. Oxygen sufficiency controls TOP mRNA translation via the TSC-Rheb-mTOR pathway in a 4E-BP-independent manner. J. Mol. Cell Biol. 10.1093/jmcb/mju008 (13 March 2014).

  59. Shama, S., Avni, D., Frederickson, R.M., Sonenberg, N. & Meyuhas, O. Overexpression of initiation factor eIF-4E does not relieve the translational repression of ribosomal protein mRNAs in quiescent cells. Gene Expr. 4, 241–252 (1995).

    CAS  PubMed  Google Scholar 

  60. Damgaard, C.K. & Lykke-Andersen, J. Translational coregulation of 5′TOP mRNAs by TIA-1 and TIAR. Genes Dev. 25, 2057–2068 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Tcherkezian, J. et al. Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5′TOP mRNA translation. Genes Dev. 28, 357–371 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Flynn, A. & Proud, C.G. Serine 209, not serine 53, is the major site of phosphorylation in initiation factor eIF-4E in serum-treated Chinese hamster ovary cells. J. Biol. Chem. 270, 21684–21688 (1995).

    Article  CAS  PubMed  Google Scholar 

  63. Fukunaga, R. & Hunter, T. MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J. 16, 1921–1933 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Waskiewicz, A.J., Flynn, A., Proud, C.G. & Cooper, J.A. Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J. 16, 1909–1920 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Furic, L. et al. eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression. Proc. Natl. Acad. Sci. USA 107, 14134–14139 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fernandez, P.C. et al. Genomic targets of the human c-Myc protein. Genes Dev. 17, 1115–1129 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Topisirovic, I. et al. Stability of eukaryotic translation initiation factor 4E mRNA is regulated by HuR, and this activity is dysregulated in cancer. Mol. Cell. Biol. 29, 1152–1162 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Cook, K.D. & Miller, J. TCR-dependent translational control of GATA-3 enhances Th2 differentiation. J. Immunol. 185, 3209–3216 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Gigoux, M. et al. Inducible costimulator facilitates T-dependent B cell activation by augmenting IL-4 translation. Mol. Immunol. 59, 46–54 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Lee, M.S., Kim, B., Oh, G.T. & Kim, Y.J. OASL1 inhibits translation of the type I interferon-regulating transcription factor IRF7. Nat. Immunol. 14, 346–355 (2013).This study identifies OASL1 as a key regulator of the translation of IRF7, which affects the expression of type 1 interferon. It proposes that OASL1 acts in a negative feedback loop by suppressing the translation of IRF7 mRNA.

    Article  CAS  PubMed  Google Scholar 

  71. Bjur, E. et al. Distinct translational control in CD4+ T cell subsets. PLoS Genet. 9, e1003494 (2013).This study shows that analysis of translatomes is feasible in primary cells of the immune system that are of low abundance and that such analysis provides a perspective distinct from the analysis of their transcriptomes. It also identifies eIF4E-dependent translational control as key for the proliferation of Foxp3− and Foxp3+ CD4+ T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Tangye, S.G., Ma, C.S., Brink, R. & Deenick, E.K. The good, the bad and the ugly - TFH cells in human health and disease. Nat. Rev. Immunol. 13, 412–426 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Araki, K., Ellebedy, A.H. & Ahmed, R. TOR in the immune system. Curr. Opin. Cell Biol. 23, 707–715 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xu, H. et al. Notch-RBP-J signaling regulates the transcription factor IRF8 to promote inflammatory macrophage polarization. Nat. Immunol. 13, 642–650 (2012).This study shows that phosphorylation of eIF4E is key in the translational activation of IRF8 mRNA and downstream macrophage polarization.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Herdy, B. et al. Translational control of the activation of transcription factor NF-κB and production of type I interferon by phosphorylation of the translation factor eIF4E. Nat. Immunol. 13, 543–550 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Nikolcheva, T. et al. A translational rheostat for RFLAT-1 regulates RANTES expression in T lymphocytes. J. Clin. Invest. 110, 119–126 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Krausgruber, T. et al. IRF5 promotes inflammatory macrophage polarization and TH1–TH17 responses. Nat. Immunol. 12, 231–238 (2011).

    Article  CAS  PubMed  Google Scholar 

  78. Satoh, T. et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat. Immunol. 11, 936–944 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Huang, J.T. & Schneider, R.J. Adenovirus inhibition of cellular protein synthesis involves inactivation of cap-binding protein. Cell 65, 271–280 (1991).

    Article  CAS  PubMed  Google Scholar 

  80. Kleijn, M., Vrins, C.L., Voorma, H.O. & Thomas, A.A. Phosphorylation state of the cap-binding protein eIF4E during viral infection. Virology 217, 486–494 (1996).

    Article  CAS  PubMed  Google Scholar 

  81. Connor, J.H. & Lyles, D.S. Vesicular stomatitis virus infection alters the eIF4F translation initiation complex and causes dephosphorylation of the eIF4E binding protein 4E-BP1. J. Virol. 76, 10177–10187 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Walsh, D. et al. Eukaryotic translation initiation factor 4F architectural alterations accompany translation initiation factor redistribution in poxvirus-infected cells. Mol. Cell. Biol. 28, 2648–2658 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Walsh, D., Perez, C., Notary, J. & Mohr, I. Regulation of the translation initiation factor eIF4F by multiple mechanisms in human cytomegalovirus-infected cells. J. Virol. 79, 8057–8064 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Walsh, D. & Mohr, I. Phosphorylation of eIF4E by Mnk-1 enhances HSV-1 translation and replication in quiescent cells. Genes Dev. 18, 660–672 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ben-Neriah, Y. & Karin, M. Inflammation meets cancer, with NF-κB as the matchmaker. Nat. Immunol. 12, 715–723 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Vashchenko, G. & MacGillivray, R.T. Multi-copper oxidases and human iron metabolism. Nutrients 5, 2289–2313 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Klebanoff, S.J. Bactericidal effect of Fe2+, ceruloplasmin, and phosphate. Arch. Biochem. Biophys. 295, 302–308 (1992).

    Article  CAS  PubMed  Google Scholar 

  88. Mazumder, B. & Fox, P.L. Delayed translational silencing of ceruloplasmin transcript in γ interferon-activated U937 monocytic cells: role of the 3′ untranslated region. Mol. Cell. Biol. 19, 6898–6905 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Sampath, P., Mazumder, B., Seshadri, V. & Fox, P.L. Transcript-selective translational silencing by gamma interferon is directed by a novel structural element in the ceruloplasmin mRNA 3′ untranslated region. Mol. Cell. Biol. 23, 1509–1519 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Vyas, K. et al. Genome-wide polysome profiling reveals an inflammation-responsive posttranscriptional operon in gamma interferon-activated monocytes. Mol. Cell. Biol. 29, 458–470 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Mukhopadhyay, R. et al. DAPK-ZIPK-L13a axis constitutes a negative-feedback module regulating inflammatory gene expression. Mol. Cell 32, 371–382 (2008).These authors identify a negative feedback loop for GAIT complex activity. DAPK and ZIPK, which are activators of the GAIT complex, are themselves targets for suppressed translation via a GAIT-dependent mechanism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Scheu, S. et al. Activation of the integrated stress response during T helper cell differentiation. Nat. Immunol. 7, 644–651 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Wek, R.C., Jiang, H.Y. & Anthony, T.G. Coping with stress: eIF2 kinases and translational control. Biochem. Soc. Trans. 34, 7–11 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Villarino, A.V. et al. Posttranscriptional silencing of effector cytokine mRNA underlies the anergic phenotype of self-reactive T cells. Immunity 34, 50–60 (2011).This study shows that translational control of cytokines is important for self reactive T-cell anergy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Piecyk, M. et al. TIA-1 is a translational silencer that selectively regulates the expression of TNF-α. EMBO J. 19, 4154–4163 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Katsanou, V. et al. HuR as a negative posttranscriptional modulator in inflammation. Mol. Cell 19, 777–789 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Yu, C. et al. An essential function of the SRC-3 coactivator in suppression of cytokine mRNA translation and inflammatory response. Mol. Cell 25, 765–778 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dixon, D.A. et al. Regulation of cyclooxygenase-2 expression by the translational silencer TIA-1. J. Exp. Med. 198, 475–481 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Dhamija, S. et al. Interleukin-17 (IL-17) and IL-1 activate translation of overlapping sets of mRNAs, including that of the negative regulator of inflammation, MCPIP1. J. Biol. Chem. 288, 19250–19259 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Yamamoto, M. et al. Regulation of Toll/IL-1-receptor-mediated gene expression by the inducible nuclear protein IκBζ. Nature 430, 218–222 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Chang, C.H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239–1251 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Warner, J.R., Knopf, P.M. & Rich, A. A multiple ribosomal structure in protein synthesis. Proc. Natl. Acad. Sci. USA 49, 122–129 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Johannes, G., Carter, M.S., Eisen, M.B., Brown, P.O. & Sarnow, P. Identification of eukaryotic mRNAs that are translated at reduced cap binding complex eIF4F concentrations using a cDNA microarray. Proc. Natl. Acad. Sci. USA 96, 13118–13123 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Karginov, F.V. & Hannon, G.J. Remodeling of Ago2-mRNA interactions upon cellular stress reflects miRNA complementarity and correlates with altered translation rates. Genes Dev. 27, 1624–1632 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ingolia, N.T., Ghaemmaghami, S., Newman, J.R. & Weissman, J.S. Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science 324, 218–223 (2009).This study introduces the ribosome-profiling technique as a genome-wide tool with which to map the positions of ribosomes on mRNA.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Ingolia, N.T., Brar, G.A., Rouskin, S., McGeachy, A.M. & Weissman, J.S. The ribosome profiling strategy for monitoring translation in vivo by deep sequencing of ribosome-protected mRNA fragments. Nat. Protoc. 7, 1534–1550 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zoschke, R., Watkins, K.P. & Barkan, A. A rapid ribosome profiling method elucidates chloroplast ribosome behavior in vivo. Plant Cell 25, 2265–2275 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Larsson, O., Sonenberg, N. & Nadon, R. Identification of differential translation in genome wide studies. Proc. Natl. Acad. Sci. USA 107, 21487–21492 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Olshen, A.B. et al. Assessing gene-level translational control from ribosome profiling. Bioinformatics 29, 2995–3002 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Larsson, O & Nadon, R. Re-analysis of genome wide data on mammalian microRNA-mediated suppression of gene expression. Translation 1, 1–9 (2013).

    Article  Google Scholar 

  111. Eliseeva, I.A., Vorontsov, I.E., Babeyev, K.E., Buyanova, S.M., Sysoeva, M.A. & Kondrashov, F.A. et al. In silico motif analysis suggests an interplay of transcriptional and translational control in mTOR response. Translation 1, 1–7 (2013).

    Article  Google Scholar 

  112. Larsson, O., Sonenberg, N. & Nadon, R. Anota: Analysis of differential translation in genome-wide studies. Bioinformatics 27, 1440–1441 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Colman, H. et al. Genome-wide analysis of host mRNA translation during hepatitis C virus infection. J. Virol. 87, 6668–6677 (2013).This article shows that the analysis approach (Anota or translational-efficiency score) is critical for predicting whether differences in translation identified will correlate with changes in proteomes. Only Anota analysis corresponds to changes in protein amounts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Larsson, O. et al. Distinct perturbation of the translatome by the antidiabetic drug metformin. Proc. Natl. Acad. Sci. USA 109, 8977–8982 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Parker, M.W. et al. Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J. Clin. Invest. 124, 1622–1635 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Stumpf, C.R., Moreno, M.V., Olshen, A.B., Taylor, B.S. & Ruggero, D. The translational landscape of the mammalian cell cycle. Mol. Cell 52, 574–582 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tebaldi, T., Dassi, E., Kostoska, G., Viero, G. & Quattrone, A. tRanslatome: an R/Bioconductor package to portray translational control. Bioinformatics 30, 289–291 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Michel, A.M. et al. GWIPS-viz: development of a ribo-seq genome browser. Nucleic Acids Res. 42, D859–D864 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Schneider-Poetsch, T. et al. Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin. Nat. Chem. Biol. 6, 209–217 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lee, S. et al. Global mapping of translation initiation sites in mammalian cells at single-nucleotide resolution. Proc. Natl. Acad. Sci. USA 109, E2424–E2432 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Ingolia, N.T., Lareau, L.F. & Weissman, J.S. Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of Mammalian proteomes. Cell 147, 789–802 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Guttman, M., Russell, P., Ingolia, N.T., Weissman, J.S. & Lander, E.S. Ribosome profiling provides evidence that large noncoding RNAs do not encode proteins. Cell 154, 240–251 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Fresno, M., Jimenez, A. & Vazquez, D. Inhibition of translation in eukaryotic systems by harringtonine. Eur. J. Biochem. 72, 323–330 (1977).

    Article  CAS  PubMed  Google Scholar 

  124. Larsson, O. et al. Eukaryotic translation initiation factor 4E induced progression of primary human mammary epithelial cells along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors. Cancer Res. 67, 6814–6824 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Mamane, Y. et al. Epigenetic activation of a subset of mRNAs by eIF4E explains its effects on cell proliferation. PLoS ONE 2, e242 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Rajasekhar, V.K. et al. Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol. Cell 12, 889–901 (2003).

    Article  CAS  PubMed  Google Scholar 

  127. Tominaga, Y., Tamguney, T., Kolesnichenko, M., Bilanges, B. & Stokoe, D. Translational deregulation in PDK-1−/− embryonic stem cells. Mol. Cell. Biol. 25, 8465–8475 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Mikulits, W. et al. Isolation of translationally controlled mRNAs by differential screening. FASEB J. 14, 1641–1652 (2000).

    Article  CAS  PubMed  Google Scholar 

  129. Grolleau, A. et al. Global and specific translational control by rapamycin in T cells uncovered by microarrays and proteomics. J. Biol. Chem. 277, 22175–22184 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Ceppi, M. et al. Ribosomal protein mRNAs are translationally-regulated during human dendritic cells activation by LPS. Immunome Res. 5, 5 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Kitamura, H. et al. Genome-wide identification and characterization of transcripts translationally regulated by bacterial lipopolysaccharide in macrophage-like J774.1 cells. Physiol. Genomics 33, 121–132 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Ring, A.M. et al. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nat. Immunol. 13, 1187–1195 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Supported by the Canadian Institutes for Health Research (I.T., and MOP 67211 to C.A.P.), the Canada Research Chair program (C.A.P.), the Swedish Research Council (O.L.), the Swedish Cancer Society (O.L.) and the Wallenberg Academy Fellows program (O.L.).

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, and Microbiome and Disease Tolerance Centre, McGill University, Montreal, Canada

    Ciriaco A Piccirillo

  2. FOCIS Centre of Excellence and Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montreal, Canada

    Ciriaco A Piccirillo

  3. Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden

    Eva Bjur & Ola Larsson

  4. Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montréal, Canada

    Ivan Topisirovic

  5. Department of Oncology, McGill University, Montréal, Canada

    Ivan Topisirovic

  6. Department of Biochemistry, and Goodman Cancer Research Centre, McGill University, Montreal, Canada

    Nahum Sonenberg

Authors
  1. Ciriaco A Piccirillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eva Bjur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ivan Topisirovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nahum Sonenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ola Larsson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Ciriaco A Piccirillo or Ola Larsson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Piccirillo, C., Bjur, E., Topisirovic, I. et al. Translational control of immune responses: from transcripts to translatomes. Nat Immunol 15, 503–511 (2014). https://doi.org/10.1038/ni.2891

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.2891

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing