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Diversity and selectivity in mRNA translation on the endoplasmic reticulum

Key Points

  • Ribosomes bound to the endoplasmic reticulum (ER) membrane translate a large and diverse population of mRNAs.

  • Many mechanisms, including ribosome and mRNA binding, contribute to the recruitment of translation to the ER.

  • Ribosomes and mRNAs associate with the ER over many successive rounds of protein synthesis.

  • The ER and cytosol are distinct compartments for protein translation and post-transcriptional gene regulation.

  • Localization of an mRNA can be an important regulatory variable during cell stress.

Abstract

Pioneering electron microscopy studies defined two primary populations of ribosomes in eukaryotic cells: one freely dispersed through the cytoplasm and the other bound to the surface of the endoplasmic reticulum (ER). Subsequent investigations revealed a specialized function for each population, with secretory and integral membrane protein-encoding mRNAs translated on ER-bound ribosomes, and cytosolic protein synthesis was widely attributed to free ribosomes. Recent findings have challenged this view, and transcriptome-scale studies of mRNA distribution and translation have now demonstrated that ER-bound ribosomes also function in the translation of a large fraction of mRNAs that encode cytosolic proteins. These studies suggest a far more expansive role for the ER in transcriptome expression, where membrane and secretory protein synthesis represents one element of a multifaceted and dynamic contribution to post-transcriptional gene expression.

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Figure 1: Revisiting translational compartmentalization.
Figure 2: Distribution of protein synthesis between the cytosol and the ER.
Figure 3: Assembling the translation machinery on the ER.
Figure 4: The ER as a global mRNA translation and regulation hub.

References

  1. Caro, L. G. & Palade, G. E. Protein synthesis, storage, and discharge in the pancreatic exocrine cell. An. Autoradiogr. Study. J. Cell Biol. 20, 473–495 (1964).

    CAS  PubMed  Google Scholar 

  2. Johnson, A. E. & van Waes, M. A. The translocon: a dynamic gateway at the ER membrane. Annu. Rev. Cell Dev. Biol. 15, 799–842 (1999).

    PubMed  Google Scholar 

  3. Palade, G. Intracellular aspects of the process of protein synthesis. Science 189, 347–358 (1975). This paper provides an important overview of the early understanding of the field and a summary of outstanding questions.

    CAS  PubMed  Google Scholar 

  4. Rapoport, T. A. Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes. Nature 450, 663–669 (2007).

    CAS  PubMed  Google Scholar 

  5. Blobel, G. Protein targeting (Nobel lecture). Chembiochem 1, 86–102 (2000).

    CAS  PubMed  Google Scholar 

  6. Walter, P. & Johnson, A. E. Signal sequence recognition and protein targeting to the endoplasmic reticulum membrane. Annu. Rev. Cell Biol. 10, 87–119 (1994).

    CAS  PubMed  Google Scholar 

  7. Cross, B. C., Sinning, I., Luirink, J. & High, S. Delivering proteins for export from the cytosol. Nature Rev. Mol. Cell Biol. 10, 255–264 (2009).

    CAS  Google Scholar 

  8. Walter, P. & Blobel, G. 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, 551–556 (1981). This landmark study reports the discovery of the SRP mechanism of cytosol-to-ER mRNA localization.

    CAS  PubMed  Google Scholar 

  9. Walter, P., Ibrahimi, I. & Blobel, G. Translocation of proteins across the endoplasmic reticulum. I. Signal recognition protein (SRP) binds to in-vitro-assembled polysomes synthesizing secretory protein. J. Cell Biol. 91, 545–550 (1981).

    CAS  PubMed  Google Scholar 

  10. Noriega, T. R., Chen, J., Walter, P. & Puglisi, J. D. Real-time observation of signal recognition particle binding to actively translating ribosomes. Elife 3, e04418 (2014).

    PubMed Central  Google Scholar 

  11. Gilmore, R., Blobel, G. & Walter, P. Protein translocation across the endoplasmic reticulum. I. Detection in the microsomal membrane of a receptor for the signal recognition particle. J. Cell Biol. 95, 461–469 (1982).

    Google Scholar 

  12. Meyer, D. I., Krause, E. & Dobberstein, B. Secretory protein translocation across membranes-the role of the 'docking protein'. Nature 297, 647–650 (1982).

    CAS  PubMed  Google Scholar 

  13. Blobel, G. & Dobberstein, B. Transfer of proteins across membranes. I. Presence of proteolytically processed and unprocessed nascent immunoglobulin light chains on membrane-bound ribosomes of murine myeloma. J. Cell Biol. 67, 835–851 (1975).

    CAS  PubMed  Google Scholar 

  14. Siekevitz, P. & Palade, G. E. A cytochemical study on the pancreas of the guinea pig. 5. In vivo incorporation of leucine-1-C14 into the chymotrypsinogen of various cell fractions. J. Biophys. Biochem. Cytol. 7, 619–630 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Potter, M. D., Seiser, R. M. & Nicchitta, C. V. Ribosome exchange revisited: a mechanism for translation-coupled ribosome detachment from the ER membrane. Trends Cell Biol. 11, 112–115 (2001).

    CAS  PubMed  Google Scholar 

  16. Seiser, R. M. & Nicchitta, C. V. The fate of membrane-bound ribosomes following the termination of protein synthesis. J. Biol. Chem. 275, 33820–33827 (2000).

    CAS  PubMed  Google Scholar 

  17. Potter, M. D. & Nicchitta, C. V. Regulation of ribosome detachment from the mammalian endoplasmic reticulum membrane. J. Biol. Chem. 275, 33828–33835 (2000).

    CAS  PubMed  Google Scholar 

  18. Reid, D. W., Chen, Q., Tay, A. S., Shenolikar, S. & Nicchitta, C. V. The unfolded protein response triggers selective mRNA release from the endoplasmic reticulum. Cell 158, 1362–1374 (2014). This study identifies a role for dynamic ER mRNA localization in cellular stress responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Palade, G. E. A small particulate component of the cytoplasm. J. Biophys. Biochem. Cytol. 1, 59–68 (1955).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hicks, S. J., Drysdale, J. W. & Munro, H. N. Preferential synthesis of ferritin and albumin by different populations of liver polysomes. Science 164, 584–585 (1969).

    CAS  PubMed  Google Scholar 

  21. Mueckler, M. M. & Pitot, H. C. Structure and function of rat liver polysome populations. I. Complexity, frequency distribution, and degree of uniqueness of free and membrane-bound polysomal polyadenylate-containing RNA populations. J. Cell Biol. 90, 495–506 (1981).

    CAS  PubMed  Google Scholar 

  22. Mechler, B. & Vassalli, P. 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 (1975).

    CAS  PubMed  Google Scholar 

  23. Mechler, B. & Vassalli, P. Membrane-bound ribosomes of myeloma cells. II. Kinetic studies on the entry of newly made ribosomal subunits into the free and the membrane-bound ribosomal particles. J. Cell Biol. 67, 16–24 (1975).

    CAS  PubMed  Google Scholar 

  24. Kopczynski, C. C. et al. A high throughput screen to identify secreted and transmembrane proteins involved in Drosophila embryogenesis. Proc. Natl Acad. Sci. USA 95, 9973–9978 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Diehn, M., Eisen, M. B., Botstein, D. & Brown, P. O. Large-scale identification of secreted and membrane-associated gene products using DNA microarrays. Nature Genet. 25, 58–62 (2000).

    CAS  PubMed  Google Scholar 

  26. Diehn, M., Bhattacharya, R., Botstein, D. & Brown, P. O. Genome-scale identification of membrane-associated human mRNAs. PLoS Genet. 2, e11 (2006).

    PubMed  PubMed Central  Google Scholar 

  27. Lerner, R. S. et al. Partitioning and translation of mRNAs encoding soluble proteins on membrane-bound ribosomes. RNA 9, 1123–1137 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Reid, D. W. & Nicchitta, C. V. Primary role for endoplasmic reticulum-bound ribosomes in cellular translation identified by ribosome profiling. J. Biol. Chem. 287, 5518–5527 (2012). This report defines the translation that occurs on cytosolic and ER-bound ribosomes during homeostasis and cell stress.

    CAS  PubMed  Google Scholar 

  29. Stephens, S. B., Dodd, R. D., Lerner, R. S., Pyhtila, B. M. & Nicchitta, C. V. Analysis of mRNA partitioning between the cytosol and endoplasmic reticulum compartments of mammalian cells. Methods Mol. Biol. 419, 197–214 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Jagannathan, S., Nwosu, C. & Nicchitta, C. V. Analyzing mRNA localization to the endoplasmic reticulum via cell fractionation. Methods Mol. Biol. 714, 301–321 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Jagannathan, S., Reid, D. W., Cox, A. H. & Nicchitta, C. V. De novo translation initiation on membrane-bound ribosomes as a mechanism for localization of cytosolic protein mRNAs to the endoplasmic reticulum. RNA 120, 489–498 (2014). This paper presents findings that translation initiation occurs on the ER.

    Google Scholar 

  32. Martin, K. C. & Ephrussi, A. mRNA localization: gene expression in the spatial dimension. Cell 136, 719–730 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Palacios, I. M. & Johnston, D. S. Getting the message across: the intracellular localization of mRNAs in higher eukaryotes. Annu. Rev. Cell Dev. Biol. 17, 569–614 (2001).

    CAS  PubMed  Google Scholar 

  34. Cui, X. A., Zhang, Y., Hong, S. J. & Palazzo, A. F. Identification of a region within the placental alkaline phosphatase mRNA that mediates p180-dependent targeting to the endoplasmic reticulum. J. Biol. Chem. 288, 29633–29641 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Loya, A. et al. The 3′-UTR mediates the cellular localization of an mRNA encoding a short plasma membrane protein. RNA 14, 1352–1365 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Nicchitta, C. V., Lerner, R. S., Stephens, S. B., Dodd, R. D. & Pyhtila, B. Pathways for compartmentalizing protein synthesis in eukaryotic cells: the template-partitioning model. Biochem. Cell Biol. 83, 687–695 (2005).

    CAS  PubMed  Google Scholar 

  37. Pyhtila, B. et al. Signal sequence- and translation-independent mRNA localization to the endoplasmic reticulum. RNA 14, 445–453 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhou, C. et al. Organelle-based aggregation and retention of damaged proteins in asymmetrically dividing cells. Cell 159, 530–542 (2014). This study identifies a distinct protein folding and aggregation environment on the ER.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Krogh, A., Larsson, B., von Heijne, G. & Sonnhammer, E. L. Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes. J. Mol. Biol. 305, 567–580 (2001).

    CAS  PubMed  Google Scholar 

  40. Mueckler, M. M. & Pitot, H. C. Structure and function of rat liver polysome populations. II. Characterization of polyadenylate-containing mRNA associated with subpopulations of membrane-bound particles. J. Cell Biol. 94, 297–307 (1982).

    CAS  PubMed  Google Scholar 

  41. Mechler, B. & Rabbitts, T. H. Membrane-bound ribosomes of myeloma cells. IV. mRNA complexity of free and membrane-bound polysomes. J. Cell Biol. 88, 29–36 (1981).

    CAS  PubMed  Google Scholar 

  42. Chen, Q., Jagannathan, S., Reid, D. W., Zheng, T. & Nicchitta, C. V. Hierarchical regulation of mRNA partitioning between the cytoplasm and the endoplasmic reticulum of mammalian cells. Mol. Biol. Cell 22, 2646–2658 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Jagannathan, S. et al. Multifunctional roles for the protein translocation machinery in RNA anchoring to the endoplasmic reticulum. J. Biol. Chem. 289, 25907–25924 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Unsworth, H., Raguz, S., Edwards, H. J., Higgins, C. F. & Yague, E. mRNA escape from stress granule sequestration is dictated by localization to the endoplasmic reticulum. FASEB J. 24, 3370–3380 (2010).

    CAS  PubMed  Google Scholar 

  45. Williams, C. C., Jan, C. H. & Weissman, J. S. Targeting and plasticity of mitochondrial proteins revealed by proximity-specific ribosome profiling. Science 346, 748–751 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Dudek, J., Rehling, P. & van der Laan, M. Mitochondrial protein import: common principles and physiological networks. Biochim. Biophys. Acta 1833, 274–285 (2013).

    CAS  PubMed  Google Scholar 

  47. Johnson, N., Powis, K. & High, S. Post-translational translocation into the endoplasmic reticulum. Biochim. Biophys. Acta 1833, 2403–2409 (2013).

    CAS  PubMed  Google Scholar 

  48. Zhou, W., Brush, M. H., Choy, M. S. & Shenolikar, S. Association with endoplasmic reticulum promotes proteasomal degradation of GADD34 protein. J. Biol. Chem. 286, 21687–21696 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Brush, M. H., Weiser, D. C. & Shenolikar, S. Growth arrest and DNA damage-inducible protein GADD34 targets protein phosphatase 1α to the endoplasmic reticulum and promotes dephosphorylation of the α subunit of eukaryotic translation initiation factor 2. Mol. Cell. Biol. 23, 1292–1303 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Jousse, C. et al. Inhibition of a constitutive translation initiation factor 2α phosphatase, CReP, promotes survival of stressed cells. J. Cell Biol. 163, 767–775 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Li, S. et al. MicroRNAs inhibit the translation of target mRNAs on the endoplasmic reticulum in Arabidopsis. Cell 153, 562–574 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Schwarz, D. S. & Blower, M. D. The calcium-dependent ribonuclease XendoU promotes ER network formation through local RNA degradation. J. Cell Biol. 207, 41–57 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hollien, J. & Weissman, J. S. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313, 104–107 (2006).

    CAS  PubMed  Google Scholar 

  54. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. & Mori, K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107, 881–891 (2001).

    CAS  PubMed  Google Scholar 

  55. Batlle, M., Marsellach, F. X., Huertas, D. & Azorin, F. Drosophila vigilin, DDP1, localises to the cytoplasm and associates to the rough endoplasmic reticulum. Biochim. Biophys. Acta 1809, 46–55 (2011).

    CAS  PubMed  Google Scholar 

  56. Stalder, L. et al. The rough endoplasmatic reticulum is a central nucleation site of siRNA-mediated RNA silencing. EMBO J. 32, 1115–1127 (2013). This report defines the ER as essential for the execution of siRNA function.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. O'Brien, E. P., Vendruscolo, M. & Dobson, C. M. Kinetic modelling indicates that fast-translating codons can coordinate cotranslational protein folding by avoiding misfolded intermediates. Nature Commun. 5, 2988 (2014).

    Google Scholar 

  58. Fedorov, A. N. & Baldwin, T. O. Contribution of cotranslational folding to the rate of formation of native protein structure. Proc. Natl Acad. Sci. USA 92, 1227–1231 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Negrutskii, B. S. & Deutscher, M. P. Channeling of aminoacyl-tRNA for protein synthesis in vivo. Proc. Natl Acad. Sci. USA 88, 4991–4995 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Negrutskii, B. S. & Deutscher, M. P. A sequestered pool of aminoacyl-tRNA in mammalian cells. Proc. Natl Acad. Sci. USA 89, 3601–3604 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Stephens, S. B. & Nicchitta, C. V. Divergent regulation of protein synthesis in the cytosol and endoplasmic reticulum compartments of mammalian cells. Mol. Biol. Cell 19, 623–632 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. David, A. et al. RNA binding targets aminoacyl-tRNA synthetases to translating ribosomes. J. Biol. Chem. 286, 20688–20700 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. McCloskey, M. A. & Poo, M. M. Rates of membrane-associated reactions: reduction of dimensionality revisited. J. Cell Biol. 102, 88–96 (1986).

    CAS  PubMed  Google Scholar 

  64. Saks, V., Beraud, N. & Wallimann, T. Metabolic compartmentation — a system level property of muscle cells: real problems of diffusion in living cells. Int. J. Mol. Sci. 9, 751–767 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Hudder, A., Nathanson, L. & Deutscher, M. P. Organization of mammalian cytoplasm. Mol. Cell. Biol. 23, 9318–9326 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Walter, P. & Blobel, G. Translocation of proteins across the endoplasmic reticulum III. Signal recognition protein (SRP) causes signal sequence-dependent and site-specific arrest of chain elongation that is released by microsomal membranes. J. Cell Biol. 91, 557–561 (1981).

    CAS  PubMed  Google Scholar 

  67. Walter, P. & Blobel, G. Translocation of proteins across the endoplasmic reticulum. Oncodev. Biol. Med. 4, 137–146 (1982).

    CAS  PubMed  Google Scholar 

  68. Rapoport, T. A. Protein transport across the endoplasmic reticulum membrane. FEBS J. 275, 4471–4478 (2008).

    CAS  PubMed  Google Scholar 

  69. Zimmermann, R., Eyrisch, S., Ahmad, M. & Helms, V. Protein translocation across the ER membrane. Biochim. Biophys. Acta 1808, 912–924 (2011).

    CAS  PubMed  Google Scholar 

  70. Stephens, S. B. et al. Stable ribosome binding to the endoplasmic reticulum enables compartment-specific regulation of mRNA translation. Mol. Biol. Cell 16, 5819–5831 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Beckmann, R. et al. Architecture of the protein-conducting channel associated with the translating 80S ribosome. Cell 107, 361–372 (2001).

    CAS  PubMed  Google Scholar 

  72. Gorlich, D. & Rapoport, T. A. Protein translocation into proteoliposomes reconstituted from purified components of the endoplasmic reticulum membrane. Cell 75, 615–630 (1993).

    CAS  PubMed  Google Scholar 

  73. Menetret, J. F. et al. Single copies of Sec61 and TRAP associate with a nontranslating mammalian ribosome. Structure 16, 1126–1137 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Voorhees, R. M., Fernandez, I. S., Scheres, S. H. & Hegde, R. S. Structure of the mammalian ribosome-Sec61 complex to 3.4 Å resolution. Cell 157, 1632–1643 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Simon, S. M. & Blobel, G. A protein-conducting channel in the endoplasmic reticulum. Cell 65, 371–380 (1991).

    CAS  PubMed  Google Scholar 

  76. Borgese, D., Blobel, G. & Sabatini, D. D. In vitro exchange of ribosomal subunits between free and membrane-bound ribosomes. J. Mol. Biol. 74, 415–438 (1973).

    CAS  PubMed  Google Scholar 

  77. Borgese, N., Mok, W., Kreibich, G. & Sabatini, D. D. Ribosomal-membrane interaction: in vitro binding of ribosomes to microsomal membranes. J. Mol. Biol. 88, 559–580 (1974).

    CAS  PubMed  Google Scholar 

  78. Savitz, A. J. & Meyer, D. I. Identification of a ribosome receptor in the rough endoplasmic reticulum. Nature 346, 540–544 (1990).

    CAS  PubMed  Google Scholar 

  79. Savitz, A. J. & Meyer, D. I. 180 kD ribosome receptor is essential for both ribosome binding and protein translocation. J. Cell Biol. 120, 853–863 (1993).

    CAS  PubMed  Google Scholar 

  80. Collins, P. G. & Gilmore, R. Ribosome binding to the endoplasmic reticulum — a 180 kD protein identified by crosslinking to membrane-bound ribosomes is not required for ribosome binding activity. J. Cell Biol. 114, 639–649 (1991).

    CAS  PubMed  Google Scholar 

  81. Nunnari, J. M., Zimmerman, D. L., Ogg, S. C. & Walter, P. Characterization of the rough endoplasmic reticulum ribosome-binding activity. Nature 352, 638–640 (1991).

    CAS  PubMed  Google Scholar 

  82. Prinz, A., Behrens, C., Rapoport, T. A., Hartmann, E. & Kalies, K. U. Evolutionarily conserved binding of ribosomes to the translocation channel via the large ribosomal RNA. EMBO J. 19, 1900–1906 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Görlich, D., Prehn, S., Hartmann, E., Kalies, K.-U. & Rapoport, T. A. A mammalian homolog of Sec61p and SecYp is associated with ribosomes and nascent polypeptides during translocation. Cell 71, 489–503 (1992).

    PubMed  Google Scholar 

  84. Kalies, K. U., Gorlich, D. & Rapoport, T. A. Binding of ribosomes to the rough endoplasmic reticulum mediated by the Sec61p-complex. J. Cell Biol. 126, 925–934 (1994).

    CAS  PubMed  Google Scholar 

  85. Schaletzky, J. & Rapoport, T. A. Ribosome binding to and dissociation from translocation sites of the endoplasmic reticulum membrane. Mol. Biol. Cell 17, 3860–3869 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Murphy, E. C. I., Zheng, T. & Nicchitta, C. V. Identification of a novel stage of ribosome/nascent chain association with the endoplasmic reticulum membrane. J. Cell Biol. 136, 1213–1226 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Kreibich, G., Freienstein, C. M., Pereyra, B. N., Ulrich, B. L. & Sabatini, D. D. Proteins of rough microsomal membranes related to ribosome binding. II. Cross-linking of bound ribosomes to specific membrane proteins exposed at the binding sites. J. Cell Biol. 77, 488–506 (1978).

    CAS  PubMed  Google Scholar 

  88. Kreibich, G., Ulrich, B. L. & Sabatini, D. D. Proteins of rough microsomal membranes related to ribosome binding. I. Identification of ribophorins I and II, membrane proteins characteristics of rough microsomes. J. Cell Biol. 77, 464–487 (1978).

    CAS  PubMed  Google Scholar 

  89. Harada, Y., Li, H., Li, H. & Lennarz, W. J. Oligosaccharyltransferase directly binds to ribosome at a location near the translocon-binding site. Proc. Natl Acad. Sci. USA 106, 6945–6949 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Yu, Y. H., Sabatini, D. D. & Kreibich, G. Antiribophorin antibodies inhibit the targeting to the ER membrane of ribosomes containing nascent secretory polypeptides. J. Cell Biol. 111, 1335–1342 (1990).

    CAS  PubMed  Google Scholar 

  91. Levy, R., Wiedmann, M. & Kreibich, G. In vitro binding of ribosomes to the β subunit of the Sec61p protein translocation complex. J. Biol. Chem. 276, 2340–2346 (2001).

    CAS  PubMed  Google Scholar 

  92. Muller, L. et al. Evolutionary gain of function for the ER membrane protein Sec62 from yeast to humans. Mol. Biol. Cell 21, 691–703 (2010).

    PubMed  PubMed Central  Google Scholar 

  93. Blau, M. et al. ERj1p uses a universal ribosomal adaptor site to coordinate the 80S ribosome at the membrane. Nature Struct. Mol. Biol. 12, 1015–1016 (2005).

    CAS  Google Scholar 

  94. Ueno, T., Kaneko, K., Sata, T., Hattori, S. & Ogawa-Goto, K. Regulation of polysome assembly on the endoplasmic reticulum by a coiled-coil protein, 180. Nucleic Acids Res. 40, 3006–3017 (2012). This paper provides a thorough analysis of the potential impact of p180 in regulating ribosome binding to the ER.

    CAS  PubMed  Google Scholar 

  95. Mauro, V. P. & Edelman, G. M. The ribosome filter hypothesis. Proc. Natl Acad. Sci. USA 99, 12031–12036 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Potter, M. D. & Nicchitta, C. V. Endoplasmic reticulum ribosomes reside in stable association with the translocon following termination of protein synthesis. J. Biol. Chem. 277, 23314–23320 (2002).

    CAS  PubMed  Google Scholar 

  97. Jan, C. H., Williams, C. C. & Weissman, J. S. Principles of ER cotranslational translocation revealed by proximity-specific ribosome profiling. Science 346, 1257521 (2014).

    PubMed  PubMed Central  Google Scholar 

  98. Kraut-Cohen, J. et al. Translation- and SRP-independent mRNA targeting to the endoplasmic reticulum in the yeast Saccharomyces cerevisiae. Mol. Biol. Cell 24, 3069–3084 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Decatur, W. A. & Fournier, M. J. rRNA modifications and ribosome function. Trends Biochem. Sci. 27, 344–351 (2002).

    CAS  PubMed  Google Scholar 

  100. Ovodov, SYu. & Alakhov, YuB. mRNA acetylated at 2′-OH-groups of ribose residues is functionally active in the cell-free translation system from wheat embryos. FEBS Lett. 270, 111–114 (1990).

    CAS  PubMed  Google Scholar 

  101. Cui, X. A., Zhang, H. & Palazzo, A. F. p180 promotes the ribosome-independent localization of a subset of mRNA to the endoplasmic reticulum. PLoS Biol. 10, e1001336 (2012). This report identifies a role for p180 in promoting selective mRNA localization.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Hortsch, M., Avossa, D. & Meyer, D. I. Characterization of secretory protein translocation: ribosome-membrane interaction in endoplasmic reticulum. J. Cell Biol. 103, 241–253 (1986).

    CAS  PubMed  Google Scholar 

  103. Ueno, T. et al. Enhancement of procollagen biosynthesis by p180 through augmented ribosome association on the endoplasmic reticulum in response to stimulated secretion. J. Biol. Chem. 285, 29941–29950 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang, H. & Stefanovic, B. Role of LARP6 and nonmuscle myosin in partitioning of collagen mRNAs to the ER membrane. PLoS ONE 9, e108870 (2014).

    PubMed  PubMed Central  Google Scholar 

  105. Polyansky, A. A., Hlevnjak, M. & Zagrovic, B. Analogue encoding of physicochemical properties of proteins in their cognate messenger RNAs. Nature Commun. 4, 2784 (2013). This paper provides a statistical approach that links the chemical properties of mRNAs and their encoded proteins to ER localization.

    Google Scholar 

  106. Prilusky, J. & Bibi, E. Studying membrane proteins through the eyes of the genetic code revealed a strong uracil bias in their coding mRNAs. Proc. Natl Acad. Sci. USA 106, 6662–6666 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. del Alamo, M. et al. Defining the specificity of cotranslationally acting chaperones by systematic analysis of mRNAs associated with ribosome-nascent chain complexes. PLoS Biol. 9, e1001100 (2011). This report demonstrates that loss of the SRP does not compromise mRNA localization at a transcriptome scale.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Mutka, S. C. & Walter, P. Multifaceted physiological response allows yeast to adapt to the loss of the signal recognition particle-dependent protein-targeting pathway. Mol. Biol. Cell 12, 577–588 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Ren, Y. G. et al. Differential regulation of the TRAIL death receptors DR4 and DR5 by the signal recognition particle. Mol. Biol. Cell 15, 5064–5074 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).

    CAS  PubMed  Google Scholar 

  111. Lee, K. et al. IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev. 16, 452–466 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Aragon, T. et al. Messenger RNA targeting to endoplasmic reticulum stress signalling sites. Nature 457, 736–740 (2009).

    CAS  PubMed  Google Scholar 

  113. Yanagitani, K. et al. Cotranslational targeting of XBP1 protein to the membrane promotes cytoplasmic splicing of its own mRNA. Mol. Cell 34, 191–200 (2009).

    CAS  PubMed  Google Scholar 

  114. Gaddam, D., Stevens, N. & Hollien, J. Comparison of mRNA localization and regulation during endoplasmic reticulum stress in Drosophila cells. Mol. Biol. Cell 24, 14–20 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Risco, C. et al. Endoplasmic reticulum–Golgi intermediate compartment membranes and vimentin filaments participate in vaccinia virus assembly. J. Virol. 76, 1839–1855 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Sodeik, B. et al. Assembly of vaccinia virus: role of the intermediate compartment between the endoplasmic reticulum and the Golgi stacks. J. Cell Biol. 121, 521–541 (1993).

    CAS  PubMed  Google Scholar 

  117. Desmet, E. A., Anguish, L. J. & Parker, J. S. Virus-mediated compartmentalization of the host translational machinery. mBio 5, e01463-14 (2014).

    PubMed  PubMed Central  Google Scholar 

  118. Wiest, D. L. et al. Membrane biogenesis during B cell differentiation: most endoplasmic reticulum proteins are expressed coordinately. J. Cell Biol. 110, 1501–1511 (1990).

    CAS  PubMed  Google Scholar 

  119. Blobel, G. et al. Translocation of proteins across membranes: the signal hypothesis and beyond. Symp. Soc. Exp. Biol. 33, 9–36 (1979).

    CAS  PubMed  Google Scholar 

  120. Walter, P. & Blobel, G. Purification of a membrane-associated protein complex required for protein translocation across the endoplasmic reticulum. Proc. Natl Acad. Sci. USA 77, 7112–7116 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank former members of C.V.N.'s laboratory, in particular M. Potter, R. Seiser, S. Stephens, R. Lerner and S. Jagannathan, for their many contributions to the concepts proposed in this Review, and current laboratory members, in particular J. C.-C. Hsu and A. Hoffman, for their critical feedback and contributions. They also thank S. Shenolikar for his ongoing contribution to the introduction and maturation of these ideas. Work in C.V.N.'s laboratory is supported by a grant from the National Institute of General Medical Sciences of the US National Institutes of Health (GM101533 to C.V.N.). D.W.R. is funded by a Translational Clinical Research Flagship Award entitled 'National Parkinson's Disease Translational Clinical Research Programme' from National Medical Research Council Singapore.

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Correspondence to Christopher V. Nicchitta.

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Glossary

Topogenic signal

A hydrophobic region of a protein that is targeted to the endoplasmic reticulum.

Signal recognition particle

(SRP). A ribonucleoprotein complex that targets nascent secretory and membrane proteins to the endoplasmic reticulum as they emerge from the ribosomes.

Microsomal vesicles

Vesicles that are derived from the endoplasmic reticulum and that are commonly used for in vitro studies of translation and protein translocation.

Multi-tRNA synthetase

An assembly of many tRNA synthetases that serves to concentrate the charging of tRNAs with amino acids.

Rough microsomes

Highly purified, translation-competent endoplasmic reticulum, generally obtained from canine pancreas.

Proteostasis

The status and health of protein folding in the cell.

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Reid, D., Nicchitta, C. Diversity and selectivity in mRNA translation on the endoplasmic reticulum. Nat Rev Mol Cell Biol 16, 221–231 (2015). https://doi.org/10.1038/nrm3958

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