Fidelity of the humoral immune response requires that quiescent B lymphocytes display membrane bound immunoglobulin M (IgM) on B lymphocytes surface as part of the B cell receptor, whose function is to recognize an antigen. At the same time B lymphocytes should not secrete IgM until recognition of the antigen has occurred. The heavy chains of the secretory IgM have a C-terminal tail with a cysteine instead of a membrane anchor, which serves to covalently link the IgM subunits by disulfide bonds to form “pentamers” or “hexamers.” By virtue of the same cysteine, unassembled secretory IgM subunits are recognized and retained (via mixed disulfide bonds) by members of the protein disulfide isomerase family, in particular ERp44. This so-called “thiol-mediated retention” bars assembly intermediates from prematurely leaving the cell and thereby exerts quality control on the humoral immune response. In this essay we discuss recent findings on how ERp44 governs such assembly control in a pH-dependent manner, shuttling between the cisGolgi and endoplasmic reticulum, and finally on how pERp1/MZB1, possibly as a co-chaperone of GRP94, may help to overrule the thiol-mediated retention in the activated B cell to give way to antibody secretion. 1. Introduction In the arms race between pathogens and hosts, vertebrates developed a long-range weapon of high precision: the antibody. Antibodies are produced by activated B lymphocytes. Once they are secreted, the antibodies spread throughout the organism to recognize and bind to specific epitopes on pathogens. As such, the pathogens are stigmatized as a target for complement or phagocyte mediated attack and (if all is well) elimination. All weaponry is hazardous, because of the risk that it may “go off” at the wrong moment and aim at the wrong target. Thus, it comes as no surprise that the immune system is reined in by a wealth of safety measures (unfortunately, they are not always fail-proof as the prevalence of autoimmune diseases illustrates). Safety dictates that B lymphocytes should not secrete antibodies, unless there is a confirmed sighting of an antigen, that is, when there is a good match between the antigen and the particular antibody which the B lymphocyte happens to express on its surface. At that moment, the B lymphocyte commits to become a plasma cell, which arguably is one of the most prolific secretory cells in the metazoan kingdom as it releases in bulk the antibody that specifically targets that very antigen. How can it be that the same cell that first obstinately prevents antibodies from leaking out makes
References
[1]
L. M. Hendershot and R. Sitia, “Immunoglobulin assembly and secretion,” in Molecular Biology of B Cells, T. Honjo, F. W. Alt, and M. S. Neuberger, Eds., pp. 261–273, Elsevier Academic Press, Amsterdam, The Netherlands, 2005.
[2]
R. Sitia, M. Neuberger, C. Alberini et al., “Developmental regulation of IgM secretion: the role of the carboxy-terminal cysteine,” Cell, vol. 60, no. 5, pp. 781–790, 1990.
[3]
I. Braakman and N. J. Bulleid, “Protein folding and modification in the mammalian endoplasmic reticulum,” Annual Review of Biochemistry, vol. 80, pp. 71–99, 2011.
[4]
I. G. Haas and M. Wabl, “Immunoglobulin heavy chain binding protein,” Nature, vol. 306, no. 5941, pp. 387–389, 1983.
[5]
J. Melnick, S. Aviel, and Y. Argon, “The endoplasmic reticulum stress protein GRP94, in addition to BiP, associates with unassembled immunoglobulin chains,” Journal of Biological Chemistry, vol. 267, no. 30, pp. 21303–21306, 1992.
[6]
P. Reddy, A. Sparvoli, C. Fagioli, G. Fassina, and R. Sitia, “Formation of reversible disulfide bonds with the protein matrix of the endoplasmic reticulum correlates with the retention of unassembled Ig light chains,” EMBO Journal, vol. 15, no. 9, pp. 2077–2085, 1996.
[7]
T. Anelli, M. Alessio, A. Bachi et al., “Thiol-mediated protein retention in the endoplasmic reticulum: the role of ERp44,” EMBO Journal, vol. 22, no. 19, pp. 5015–5022, 2003.
[8]
F. Hochstenbach, V. David, S. Watkins, and M. B. Brenner, “Endoplasmic reticulum resident protein of 90 kilodaltons associates with the T- and B-cell antigen receptors and major histocompatibility complex antigens during their assembly,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 10, pp. 4734–4738, 1992.
[9]
T. Anelli, S. Ceppi, L. Bergamelli et al., “Sequential steps and checkpoints in the early exocytic compartment during secretory IgM biogenesis,” EMBO Journal, vol. 26, no. 19, pp. 4177–4188, 2007.
[10]
Y. Shimizu, L. Meunier, and L. M. Hendershot, “pERp1 is significantly up-regulated during plasma cell differentiation and contributes to the oxidative folding of immunoglobulin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 40, pp. 17013–17018, 2009.
[11]
E. van Anken, F. Pena, N. Hafkemeijer et al., “Efficient IgM assembly and secretion require the plasma cell induced endoplasmic reticulum protein pERp1,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 40, pp. 17019–17024, 2009.
[12]
H. Flach, M. Rosenbaum, M. Duchniewicz et al., “Mzb1 protein regulates calcium homeostasis, antibody secretion, and integrin activation in innate-like B cells,” Immunity, vol. 33, no. 5, pp. 723–735, 2010.
[13]
T. Anelli and R. Sitia, “Protein quality control in the early secretory pathway,” EMBO Journal, vol. 27, no. 2, pp. 315–327, 2008.
[14]
A. Helenius and M. Aebi, “Roles of N-linked glycans in the endoplasmic reticulum,” Annual Review of Biochemistry, vol. 73, pp. 1019–1049, 2004.
[15]
E. van Anken and I. Braakman, “Versatility of the endoplasmic reticulum protein folding factory,” Critical Reviews in Biochemistry and Molecular Biology, vol. 40, no. 4, pp. 191–228, 2005.
[16]
H. R. B. Pelham, “The retention signal for soluble proteins of the endoplasmic reticulum,” Trends in Biochemical Sciences, vol. 15, no. 12, pp. 483–486, 1990.
[17]
D. W. Wilson, M. J. Lewis, and H. R. B. Pelham, “pH-dependent binding of KDEL to its receptor in vitro,” Journal of Biological Chemistry, vol. 268, no. 10, pp. 7465–7468, 1993.
[18]
M. J. Feige, S. Groscurth, M. Marcinowski et al., “An unfolded CH1 domain controls the assembly and secretion of IgG antibodies,” Molecular Cell, vol. 34, no. 5, pp. 569–579, 2009.
[19]
Y.-K. Lee, J. W. Brewer, R. Hellman, and L. M. Hendershot, “BiP and immunoglobulin light chain cooperate to control the folding of heavy chain and ensure the fidelity of immunoglobulin assembly,” Molecular Biology of the Cell, vol. 10, no. 7, pp. 2209–2219, 1999.
[20]
C. Zheng, R. C. Page, V. Das et al., “Structural characterization of carbohydrate binding by LMAN1 protein provides new insight into the endoplasmic reticulum export of factors V, (FV) and VIII (FVIII),” Journal of Biological Chemistry, vol. 288, no. 28, pp. 20499–20509, 2013.
[21]
M. Cortini and R. Sitia, “ERp44 and ERGIC-53 synergize in coupling efficiency and fidelity of IgM polymerization and secretion,” Traffic, vol. 11, no. 5, pp. 651–659, 2010.
[22]
B. Zhang, M. A. Cunningham, W. C. Nichols et al., “Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex,” Nature Genetics, vol. 34, no. 2, pp. 220–225, 2003.
[23]
B. Zhang, B. McGee, J. S. Yamaoka et al., “Combined deficiency of factor V and factor VIII is due to mutations in either LMAN1 or MCFD2,” Blood, vol. 107, no. 5, pp. 1903–1907, 2006.
[24]
S. Vavassori, M. Cortini, S. Masui et al., “A pH-regulated quality control cycle for surveillance of secretory protein assembly,” Molecular Cell, vol. 50, no. 6, pp. 783–792, 2013.
[25]
T. Anelli, M. Alessio, A. Mezghrani et al., “ERp44, a novel endoplasmic reticulum folding assistant of the thioredoxin family,” EMBO Journal, vol. 21, no. 4, pp. 835–844, 2002.
[26]
L. Wang, S. Vavassori, S. Li et al., “Crystal structure of human ERp44 shows a dynamic functional modulation by its carboxy-terminal tail,” EMBO Reports, vol. 9, no. 7, pp. 642–647, 2008.
[27]
A. Gilchrist, C. E. Au, J. Hiding et al., “Quantitative proteomics analysis of the secretory pathway,” Cell, vol. 127, no. 6, pp. 1265–1281, 2006.
[28]
C. Fagioli, A. Mezghrani, and R. Sitia, “Reduction of interchain disulfide bonds precedes the dislocation of Ig-μ chains from the endoplasmic reticulum to the cytosol for proteasomal degradation,” Journal of Biological Chemistry, vol. 276, no. 44, pp. 40962–40967, 2001.
[29]
Q. Long, T. Lei, B. Feng et al., “Peroxisome proliferator-activated receptor-γ increases adiponectin secretion via transcriptional repression of endoplasmic reticulum chaperone protein ERp44,” Endocrinology, vol. 151, no. 7, pp. 3195–3203, 2010.
[30]
Z. V. Wang, T. D. Schraw, J.-Y. Kim et al., “Secretion of the adipocyte-specific secretory protein adiponectin critically depends on thiol-mediated protein retention,” Molecular and Cellular Biology, vol. 27, no. 10, pp. 3716–3731, 2007.
[31]
S. Freyaldenhoven, Y. Li, A. M. Kocabas et al., “The role of ERp44 in maturation of serotonin transporter protein,” Journal of Biological Chemistry, vol. 287, no. 21, pp. 17801–17811, 2012.
[32]
M. Otsu, G. Bertoli, C. Fagioli et al., “Dynamic retention of Ero1α and Ero1β in the endoplasmic reticulum by interactions with PDI and ERp44,” Antioxidants and Redox Signaling, vol. 8, no. 3-4, pp. 274–282, 2006.
[33]
A. Fraldi, E. Zito, F. Annunziata et al., “Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44,” Human Molecular Genetics, vol. 17, no. 17, pp. 2610–2621, 2008.
[34]
T. Kakihana, K. Araki, S. Vavassori et al., “Dynamic regulation of Ero1alpha and Prx4 localization in the secretory pathway,” Journal of Biological Chemistry, vol. 288, pp. 29586–29594, 2013.
[35]
A. Cattaneo and M. S. Neuberger, “Polymeric immunoglobulin M is secreted by transfectants of non-lymphoid cells in the absence of immunoglobulin J chain,” EMBO Journal, vol. 6, no. 9, pp. 2753–2758, 1987.
[36]
N. J. Bulleid and L. Ellgaard, “Multiple ways to make disulfides,” Trends in Biochemical Sciences, vol. 36, no. 9, pp. 485–492, 2011.
[37]
A. Mezghrani, A. Fassio, A. Benham, T. Simmen, I. Braakman, and R. Sitia, “Manipulation of oxidative protein folding and PDI redox state in mammalian cells,” EMBO Journal, vol. 20, no. 22, pp. 6288–6296, 2001.
[38]
R. Sitia, M. S. Neuberger, and C. Milstein, “Regulation of membrane IgM expression in secretory B cells: translational and post-translational events,” EMBO Journal, vol. 6, no. 13, pp. 3969–3977, 1987.
[39]
E. van Anken, E. P. Romijn, C. Maggioni et al., “Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion,” Immunity, vol. 18, no. 2, pp. 243–253, 2003.
[40]
E. P. Romijn, C. Christis, M. Wieffer et al., “Expression clustering reveals detailed co-expression patterns of functionally related proteins during B cell differentiation: a proteomic study using a combination of one-dimensional gel electrophoresis, LC-MS/MS, and stable isotope labeling by amino acids in cell culture (SILAC),” Molecular and Cellular Proteomics, vol. 4, no. 9, pp. 1297–1310, 2005.
[41]
R. E. Hansen, M. Otsu, I. Braakman, and J. R. Winther, “Quantifying changes in the cellular thiol-disulfide status during differentiation of B cells into antibody-secreting plasma cells,” International Journal of Cell Biology, vol. 2013, Article ID 898563, 9 pages, 2013.
[42]
A. M. Oliver, F. Martin, G. L. Gartland, R. H. Carter, and J. F. Kearney, “Marginal zone B cells exhibit unique activation, proliferative and immunoglobulin secretory responses,” European Journal of Immunology, vol. 27, no. 9, pp. 2366–2374, 1997.
[43]
C. Aresté and D. J. Blackbourn, “Modulation of the immune system by Kaposi's sarcoma-associated herpesvirus,” Trends in Microbiology, vol. 17, no. 3, pp. 119–129, 2009.
[44]
L. Y. Wong, K. Brulois, Z. Toth et al., “KSHV K4. 2 immediate early gene product regulates immunoglobulin secretion and calcium homeostasis by interacting with and inhibiting pERP1,” Journal of Virology, vol. 87, no. 22, pp. 12069–12079, 2013.
[45]
S. Belkaya, S. E. Murray, J. L. Eitson, M. T. de la Morena, J. A. Forman, and N. S. van Oers, “Transgenic expression of microRNA-185 causes a developmental arrest of T cells by targeting multiple genes including Mzb1,” Journal of Biological Chemistry, vol. 288, pp. 30752–30762, 2013.
[46]
L. Belver, V. G. de Yébenes, and A. R. Ramiro, “MicroRNAs prevent the generation of autoreactive antibodies,” Immunity, vol. 33, no. 5, pp. 713–722, 2010.
[47]
M. T. de la Morena, J. L. Eitson, I. M. Dozmorov et al., “Signature MicroRNA expression patterns identified in humans with 22q11. 2 deletion/DiGeorge syndrome,” Clinical Immunology, vol. 147, no. 1, pp. 11–22, 2013.
[48]
L. J. Kobrynski and K. E. Sullivan, “Velocardiofacial syndrome, DiGeorge syndrome: the chromosome 22q11.2 deletion syndromes,” The Lancet, vol. 370, no. 9596, pp. 1443–1452, 2007.
[49]
Y. Hirate and H. Okamoto, “Canopy1, a novel regulator of FGF signaling around the midbrain-hindbrain boundary in zebrafish,” Current Biology, vol. 16, no. 4, pp. 421–427, 2006.
[50]
H. T. Do, T. V. Tselykh, J. M？kel？ et al., “Fibroblast growth factor-21 (FGF21) regulates low-density lipoprotein receptor (LDLR) levels in cells via the E3-ubiquitin ligase Mylip/Idol and the Canopy2 (Cnpy2)/Mylip-interacting saposin-like protein (Msap),” Journal of Biological Chemistry, vol. 287, no. 16, pp. 12602–12611, 2012.
[51]
K. Takahashi, T. Shibata, S. Akashi-Takamura et al., “A protein associated with Toll-like receptor (TLR) 4 (PRAT4A) is required for TLR-dependent immune responses,” Journal of Experimental Medicine, vol. 204, no. 12, pp. 2963–2976, 2007.
[52]
K. Konno, Y. Wakabayashi, S. Akashi-Takamura et al., “A molecule that is associated with Toll-like receptor 4 and regulates its cell surface expression,” Biochemical and Biophysical Research Communications, vol. 339, no. 4, pp. 1076–1082, 2006.
[53]
B. Liu, Y. Yang, Z. Qiu et al., “Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone,” Nature Communications, vol. 1, no. 79, 2012.
[54]
L. H. Pearl and C. Prodromou, “Structure and mechanism of the Hsp90 molecular chaperone machinery,” Annual Review of Biochemistry, vol. 75, pp. 271–294, 2006.
[55]
M. Marzec, D. Eletto, and Y. Argon, “GRP94: An HSP90-like protein specialized for protein folding and quality control in the endoplasmic reticulum,” Biochimica et Biophysica Acta, vol. 1823, no. 3, pp. 774–787, 2012.
[56]
C. C. Lee, A. M. Avalos, and H. L. Ploegh, “Accessory molecules for Toll-like receptors and their function,” Nature Reviews Immunology, vol. 12, no. 3, pp. 168–179, 2012.
[57]
G. W. Litman, M. F. Flajnik, and G. W. Warr, “Diverse forms of immunoglobulin genes in lower vertebrates,” in Molecular Biology of B Cells, T. Honjo, F. W. Alt, and M. S. Neuberger, Eds., pp. 417–432, Elsevier Academic Press, Amsterdam, The Netherlands, 2005.
