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Building an antibody factory: a job for the unfolded protein response

Nature Immunology volume 6, pages 23–29 (2005)Cite this article

A Corrigendum to this article was published on 01 February 2005

Abstract

Plasma cells are highly specialized, terminally differentiated secretory cells that produce tremendous quantities of a single product, the antibody molecule. In differentiating from a quiescent B cell, the plasma cell must undergo a dramatic architectural metamorphosis. This process entails augmenting the secretory organelles and the proteins that populate them, upregulating their energy and translation potential, and increasing the quality control system to do the job. This transformation is accomplished by an interplay between B lineage–specific transcriptional programs that control plasma cell differentiation and an unfolded protein response.

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Figure 1: Components of the mammalian UPR.
Figure 2: Making an antibody-producing machine.
Figure 3: Mechanisms for downregulating the PERK pathway.
Figure 4: Interplay between transcriptional programs during plasma cell differentiation.

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References

  1. Mori, K., Ma, W., Gething, M.J. & Sambrook, J. A transmembrane protein with a cdc2+/CDC28-related kinase activity is required for signalling from the ER to the nucleus. Cell 74, 743–756 (1993).

    Article  CAS  Google Scholar 

  2. Cox, J.S., Shamu, C.E. & Walter, P. Transcriptional induction of genes encoding endoplasmic reticulum resident proteins requires a transmembrane protein kinase. Cell 73, 1197–1206 (1993).

    Article  CAS  Google Scholar 

  3. Okamura, K., Kimata, Y., Higashio, H., Tsuru, A. & Kohno, K. Dissociation of Kar2p/BiP from an ER sensory molecule, Ire1p, triggers the unfolded protein response in yeast. Biochem. Biophys. Res. Commun. 279, 445–450 (2000).

    Article  CAS  Google Scholar 

  4. Sidrauski, C. & Walter, P. The transmembrane kinase Ire1p is a site-specific endonuclease that initiates mRNA splicing in the unfolded protein response. Cell 90, 1031–1039 (1997).

    Article  CAS  Google Scholar 

  5. Sidrauski, C., Cox, J.S. & Walter, P. tRNA ligase is required for regulated mRNA splicing in the unfolded protein response. Cell 87, 405–413 (1996).

    Article  CAS  Google Scholar 

  6. Travers, K.J. et al. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101, 249–258 (2000).

    Article  CAS  Google Scholar 

  7. Nikawa, J. & Yamashita, S. IRE1 encodes a putative protein kinase containing a membrane-spanning domain and is required for inositol phototrophy in Saccharomyces cerevisiae. Mol. Microbiol. 6, 1441–1446 (1992).

    Article  CAS  Google Scholar 

  8. Tirasophon, W., Welihinda, A.A. & Kaufman, R.J. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 12, 1812–1824 (1998).

    Article  CAS  Google Scholar 

  9. Wang, X.-Z. et al. Cloning of mammalian Ire1 reveals diversity in the ER stress responses. EMBO J. 17, 5708–5717 (1998).

    Article  CAS  Google Scholar 

  10. Yoshida, H., Haze, K., Yanagi, H., Yura, T. & Mori, K. 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, 33741–33749 (1998).

    Article  CAS  Google Scholar 

  11. Ye, J. et al. ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol. Cell 6, 1355–1364 (2000).

    Article  CAS  Google Scholar 

  12. Haze, K., Yoshida, H., Yanagi, H., Yura, T. & Mori, K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10, 3787–3799 (1999).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. Calfon, M. et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415, 92–96 (2002).

    Article  CAS  Google Scholar 

  15. Shaffer, A.L. et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21, 81–93 (2004).

    Article  CAS  Google Scholar 

  16. Sriburi, R., Jackowski, S., Mori, K. & Brewer, J.W. XBP1: a link between the unfolded protein response, lipid biosynthesis, and biogenesis of the endoplasmic reticulum. J. Cell Biol. 167, 35–41 (2004).

    Article  CAS  Google Scholar 

  17. Nakagawa, T. et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature 403, 98–103 (2000).

    Article  CAS  Google Scholar 

  18. Harding, H.P., Zhang, Y. & Ron, D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 397, 271–274 (1999).

    Article  CAS  Google Scholar 

  19. Harding, H.P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099–1108 (2000).

    Article  CAS  Google Scholar 

  20. Novoa, I., Zeng, H., Harding, H.P. & Ron, D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2α. J. Cell Biol. 153, 1011–1022 (2001).

    Article  CAS  Google Scholar 

  21. Ma, Y. & Hendershot, L.M. Delineation of the negative feedback regulatory loop that controls protein translation during ER stress. J. Biol. Chem. 278, 34864–34873 (2003).

    Article  CAS  Google Scholar 

  22. Brewer, J.W. & Diehl, J.A. PERK mediates cell-cycle exit during the mammalian unfolded protein response. Proc. Natl. Acad. Sci. USA 97, 12625–12630 (2000).

    Article  CAS  Google Scholar 

  23. Jiang, H.Y. et al. Phosphorylation of the α subunit of eukaryotic initiation factor 2 is required for activation of NF-κB in response to diverse cellular stresses. Mol. Cell. Biol. 23, 5651–5663 (2003).

    Article  CAS  Google Scholar 

  24. Scheuner, D. et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol. Cell 7, 1165–1176 (2001).

    Article  CAS  Google Scholar 

  25. Shohat, M., Janossy, G. & Dourmashkin, R.R. Development of rough endoplasmic reticulum in mouse splenic lymphocytes stimulated by mitogens. Eur. J. Immunol. 3, 680–687 (1973).

    Article  CAS  Google Scholar 

  26. 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).

    Article  CAS  Google Scholar 

  27. Lewis, M.J., Mazzarella, R.A. & Green, M. Structure and assembly of the endoplasmic reticulum. The synthesis of three major endoplasmic reticulum proteins during lipopolysaccharide-induced differentiation of murine lymphocytes. J. Biol. Chem. 260, 3050–3057 (1985).

    CAS  PubMed  Google Scholar 

  28. Rush, J.S., Sweitzer, T., Kent, C., Decker, G.L. & Waechter, C.J. Biogenesis of the endoplasmic reticulum in activated B lymphocytes: temporal relationships between the induction of protein N-glycosylation activity and the biosynthesis of membrane protein and phospholipid. Arch. Biochem. Biophys. 284, 63–70 (1991).

    Article  CAS  Google Scholar 

  29. van Anken, E. et al. Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion. Immunity 18, 243–253 (2003).

    Article  CAS  Google Scholar 

  30. Haas, I.G. & Wabl, M. Immunoglobulin heavy chain binding protein. Nature 306, 387–389 (1983).

    Article  CAS  Google Scholar 

  31. Hendershot, L., Bole, D., Kohler, G. & Kearney, J.F. Assembly and secretion of heavy chains that do not associate posttranslationally with immunoglobulin heavy chain–binding protein. J. Cell Biol. 104, 761–767 (1987).

    Article  CAS  Google Scholar 

  32. Hendershot, L. et al. Inhibition of immunoglobulin folding and secretion by dominant negative BiP ATPase mutants. Proc. Natl. Acad. Sci. USA 93, 5269–5274 (1996).

    Article  CAS  Google Scholar 

  33. Bulleid, N.J. & Freedman, R.B. Defective co-translational formation of disulphide bonds in protein disulphide-isomerase-deficient microsomes. Nature 335, 649–651 (1988).

    Article  CAS  Google Scholar 

  34. Anelli, T. et al. Thiol-mediated protein retention in the endoplasmic reticulum: the role of ERp44. EMBO J. 22, 5015–5022 (2003).

    Article  CAS  Google Scholar 

  35. Reddy, P.S. & Corley, R.B. The contribution of ER quality control to the biologic functions of secretory IgM. Immunol. Today 20, 582–588 (1999).

    Article  CAS  Google Scholar 

  36. Reimold, A.M. et al. An essential role in liver development for transcription factor XBP-1. Genes Dev. 14, 152–157 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Reimold, A.M. et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300–307 (2001).

    Article  CAS  Google Scholar 

  38. Iwakoshi, N.N. et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat. Immunol. 4, 321–329 (2003).

    Article  CAS  Google Scholar 

  39. Gunn, K.E., Gifford, N.M., Mori, K. & Brewer, J.W. A role for the unfolded protein response in optimizing antibody secretion. Mol. Immunol. 41, 919–927 (2004).

    Article  CAS  Google Scholar 

  40. Bertolotti, A., Zhang, Y., Hendershot, L.M., Harding, H.P. & Ron, D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat. Cell Biol. 2, 326–332 (2000).

    Article  CAS  Google Scholar 

  41. Shen, J., Chen, X., Hendershot, L. & Prywes, R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev. Cell 3, 99–111 (2002).

    Article  CAS  Google Scholar 

  42. Gass, J.N., Gifford, N.M. & Brewer, J.W. Activation of an unfolded protein response during differentiation of antibody-secreting B cells. J. Biol. Chem. 277, 49047–49054 (2002).

    Article  CAS  Google Scholar 

  43. Yoshida, H. et al. ATF6 Activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol. Cell. Biol. 20, 6755–6767 (2000).

    Article  CAS  Google Scholar 

  44. Novoa, I. et al. Stress-induced gene expression requires programmed recovery from translational repression. EMBO J. 22, 1180–1187 (2003).

    Article  CAS  Google Scholar 

  45. Harding, H.P. et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk−/− mice reveals a role for translational control in secretory cell survival. Mol. Cell 7, 1153–1163 (2001).

    Article  CAS  Google Scholar 

  46. Iwawaki, T., Akai, R., Kohno, K. & Miura, M. A transgenic mouse model for monitoring endoplasmic reticulum stress. Nat. Med. 10, 98–102 (2004).

    Article  CAS  Google Scholar 

  47. Zhang, P. et al. The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol. Cell. Biol. 22, 3864–3874 (2002).

    Article  CAS  Google Scholar 

  48. Lee, A.H., Iwakoshi, N.N. & Glimcher, L.H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23, 7448–7459 (2003).

    Article  CAS  Google Scholar 

  49. Yan, W. et al. Control of PERK eIF2alpha kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proc. Natl. Acad. Sci. USA 99, 15920–15925 (2002).

    Article  CAS  Google Scholar 

  50. van Huizen, R., Martindale, J.L., Gorospe, M. & Holbrook, N.J. P58IPK, a novel endoplasmic reticulum stress-inducible protein and potential negative regulator of eIF2α signaling. J. Biol. Chem. 278, 15558–15564 (2003).

    Article  CAS  Google Scholar 

  51. Welihinda, A.A., Tirasophon, W., Green, S.R. & Kaufman, R.J. Protein serine/threonine phosphatase Ptc2p negatively regulates the unfolded-protein response by dephosphorylating Ire1p kinase. Mol. Cell. Biol. 18, 1967–1977 (1998).

    Article  CAS  Google Scholar 

  52. Shaffer, A.L. et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199–212 (2000).

    Article  CAS  Google Scholar 

  53. Turner, C.A., Jr., Mack, D.H. & Davis, M.M. Blimp-1, a novel zinc finger–containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77, 297–306 (1994).

    Article  CAS  Google Scholar 

  54. Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607–620 (2003).

    Article  CAS  Google Scholar 

  55. Niu, H., Ye, B.H. & Dalla-Favera, R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 12, 1953–1961 (1998).

    Article  CAS  Google Scholar 

  56. Lin, K.I., Angelin-Duclos, C., Kuo, T.C. & Calame, K. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol. Cell. Biol. 22, 4771–4780 (2002).

    Article  CAS  Google Scholar 

  57. Shaffer, A.L. et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17, 51–62 (2002).

    Article  CAS  Google Scholar 

  58. Sciammas, R. & Davis, M.M. Modular nature of Blimp-1 in the regulation of gene expression during B cell maturation. J. Immunol. 172, 5427–5440 (2004).

    Article  CAS  Google Scholar 

  59. Reimold, A.M. et al. Transcription factor B cell lineage–specific activator protein regulates the gene for human X-box binding protein 1. J. Exp. Med. 183, 393–401 (1996).

    Article  CAS  Google Scholar 

  60. Lin, K.I., Lin, Y. & Calame, K. Repression of c-myc is necessary but not sufficient for terminal differentiation of B lymphocytes in vitro. Mol. Cell. Biol. 20, 8684–8695 (2000).

    Article  CAS  Google Scholar 

  61. Piskurich, J.F. et al. BLIMP-I mediates extinction of major histocompatibility class II transactivator expression in plasma cells. Nat. Immunol. 1, 526–532 (2000).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank P.D. Burrows for invaluable discussions and comments on the manuscript and W.E. Balch for providing an ingenious technical solution during the preparation of the manuscript.

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  1. Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, 60153, Illinois, USA

    Joseph W Brewer

  2. Department of Genetics and Tumor Cell Biology, St. Jude Children's Hospital, Memphis, 38105, Tennessee, USA

    Linda M Hendershot

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Correspondence to Linda M Hendershot.

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Brewer, J., Hendershot, L. Building an antibody factory: a job for the unfolded protein response. Nat Immunol 6, 23–29 (2005). https://doi.org/10.1038/ni1149

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