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Immunoglobulin transport in the absence of light chains
Update Letters
Immunoglobulin transport in the absence of light chains Daniel Corcos Institut National de la Sante´ et de la Recherche Me´dicale, INSERM Unit 955, Team 16, Universite´ Paris-Est, Faculte´ de Me´decine, UMR-S 955 Creteil, 8 Rue du Ge´ne´ral Sarrail, 94010 Cre´teil Cedex, France
In their recent TIBS article [1], Feige and colleagues place a strong emphasis on the role of the first immunoglobulin (Ig) constant domain, CH1, in preventing transport of the Ig heavy chain (HC) to the cell surface when Ig light chains are absent. This emphasis is in agreement with their own work, showing that the isolated CH1 is intrinsically disordered, as well as with numerous other data (e.g. [2]), and textbook representations of HC associated with binding immunoglobulin protein (BiP) in the endoplasmic reticulum (ER) in the absence of light chains. However, in some cases, the retention of HC might not be restricted by this domain: (i) human B cell lines that have lost light chain production but still express m chains on their surface display no alteration in the HC constant region and, instead, show a partial deletion in the variable (V) domain [3]; (ii) CH1 is often present in m heavy chain diseases (HCD), [4]; (iii) a m-HCD protein lacking the V region but containing CH1 can easily be expressed on the B cell or the pre-B cell surface in the absence of conventional [5,6] or surrogate light chains [7]. Interestingly, BiP binding sites are frequent in the HC sequence and are not restricted to CH1 [8], which indicates that a major determinant in BiP binding is actually the lack of adequate folding. Therefore, the results mentioned above suggest that the CH1 domain can fold in a way that allows HC surface deposition in the absence of light chains, and that the absence of a portion of the VH domain permits this particular type of folding. It is then possible, in agreement with the model described by Feige et al. [1], that a covalent linkage of the two cysteine residues occurs between two CH1 domains, which permits HC dimer export. Moreover, in some specific conditions, a full-length HC can be expressed at a high level on the cell surface in the absence of light chains [9–13]. The molecular requirements for transport to the surface in these instances are not known but, overall, the data indicate that, in cases in which the V domain is deleted [3–7] or when an unusual CDR3 region is present [9] or, as a consequence of ER stress (12), CH1 domains can still fold
in a way that remains to be defined, and escape BiPmediated retention. Molecules with unusual folding can thus reach the surface and, in the case of m-HCD, aggregate and signal in a manner that could be relevant to tumorigenesis [7]. References 1 Feige, M.J. et al. (2010) How antibodies fold. Trends Biochem. Sci. 35, 189–198 2 Zou, X. et al. (2007) Heavy chain-only antibodies are spontaneously produced in light chain-deficient mice. J. Exp. Med. 204, 3271– 3283 3 Pollok, B.A. et al. (1987) Molecular basis of the cell-surface expression of immunoglobulin mu chain without light chain in human B lymphocytes. Proc. Natl. Acad. Sci. U. S. A. 84, 9199–9203 4 Buxbaum, J.N. and Alexander, A. (2001) Heavy Chain Diseases, In Williams Hematology (6th edn) (Beutler, B. et al., eds), pp. 1327–1336, McGraw-Hill 5 Corcos, D. et al. (1991) Allelic exclusion in transgenic mice expressing a heavy chain disease-like human mu protein. Eur. J. Immunol. 21, 2711–2716 6 Zou, X. et al. (2008) Removal of the BiP-retention domain in Cmu permits surface deposition and developmental progression without Lchain. Mol. Immunol. 45, 3573–3579 7 Corcos, D. et al. (1995) Pre-B-cell development in the absence of lambda 5 in transgenic mice expressing a heavy-chain disease protein. Curr. Biol. 5, 1140–1148 8 Gething, M.J. (1999) Role and regulation of the ER chaperone BiP. Semin. Cell Dev. Biol. 10, 465–472 9 Minegishi, Y. and Conley, M.E. (2001) Negative selection at the preBCR checkpoint elicited by human mu heavy chains with unusual CDR3 regions. Immunity 14, 631–641 10 Su, Y.W. et al. (2003) Identification of a pre-BCR lacking surrogate light chain. J. Exp. Med. 198, 1699–1706 11 Schuh, W. et al. (2003) Cutting edge: signaling and cell surface expression of a mu H chain in the absence of lambda 5: a paradigm revisited. J. Immunol. 171, 3343–3347 12 Geraldes, P. et al. (2007) Ig heavy chain promotes mature B cell survival in the absence of light chain. J. Immunol. 179, 1659–1668 13 Corcos, D. et al. (2010) Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain. Blood 115, 282–288 0968-0004/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibs.2010.07.010 Trends in Biochemical Sciences, November 2010, Vol. 35, No. 11
Corresponding author: Corcos, D. ([email protected]).
593
Immunoglobulin transport in the absence of light chains Daniel Corcos Institut National de la Sante´ et de la Recherche Me´dicale, INSERM Unit 955, Team 16, Universite´ Paris-Est, Faculte´ de Me´decine, UMR-S 955 Creteil, 8 Rue du Ge´ne´ral Sarrail, 94010 Cre´teil Cedex, France
In their recent TIBS article [1], Feige and colleagues place a strong emphasis on the role of the first immunoglobulin (Ig) constant domain, CH1, in preventing transport of the Ig heavy chain (HC) to the cell surface when Ig light chains are absent. This emphasis is in agreement with their own work, showing that the isolated CH1 is intrinsically disordered, as well as with numerous other data (e.g. [2]), and textbook representations of HC associated with binding immunoglobulin protein (BiP) in the endoplasmic reticulum (ER) in the absence of light chains. However, in some cases, the retention of HC might not be restricted by this domain: (i) human B cell lines that have lost light chain production but still express m chains on their surface display no alteration in the HC constant region and, instead, show a partial deletion in the variable (V) domain [3]; (ii) CH1 is often present in m heavy chain diseases (HCD), [4]; (iii) a m-HCD protein lacking the V region but containing CH1 can easily be expressed on the B cell or the pre-B cell surface in the absence of conventional [5,6] or surrogate light chains [7]. Interestingly, BiP binding sites are frequent in the HC sequence and are not restricted to CH1 [8], which indicates that a major determinant in BiP binding is actually the lack of adequate folding. Therefore, the results mentioned above suggest that the CH1 domain can fold in a way that allows HC surface deposition in the absence of light chains, and that the absence of a portion of the VH domain permits this particular type of folding. It is then possible, in agreement with the model described by Feige et al. [1], that a covalent linkage of the two cysteine residues occurs between two CH1 domains, which permits HC dimer export. Moreover, in some specific conditions, a full-length HC can be expressed at a high level on the cell surface in the absence of light chains [9–13]. The molecular requirements for transport to the surface in these instances are not known but, overall, the data indicate that, in cases in which the V domain is deleted [3–7] or when an unusual CDR3 region is present [9] or, as a consequence of ER stress (12), CH1 domains can still fold
in a way that remains to be defined, and escape BiPmediated retention. Molecules with unusual folding can thus reach the surface and, in the case of m-HCD, aggregate and signal in a manner that could be relevant to tumorigenesis [7]. References 1 Feige, M.J. et al. (2010) How antibodies fold. Trends Biochem. Sci. 35, 189–198 2 Zou, X. et al. (2007) Heavy chain-only antibodies are spontaneously produced in light chain-deficient mice. J. Exp. Med. 204, 3271– 3283 3 Pollok, B.A. et al. (1987) Molecular basis of the cell-surface expression of immunoglobulin mu chain without light chain in human B lymphocytes. Proc. Natl. Acad. Sci. U. S. A. 84, 9199–9203 4 Buxbaum, J.N. and Alexander, A. (2001) Heavy Chain Diseases, In Williams Hematology (6th edn) (Beutler, B. et al., eds), pp. 1327–1336, McGraw-Hill 5 Corcos, D. et al. (1991) Allelic exclusion in transgenic mice expressing a heavy chain disease-like human mu protein. Eur. J. Immunol. 21, 2711–2716 6 Zou, X. et al. (2008) Removal of the BiP-retention domain in Cmu permits surface deposition and developmental progression without Lchain. Mol. Immunol. 45, 3573–3579 7 Corcos, D. et al. (1995) Pre-B-cell development in the absence of lambda 5 in transgenic mice expressing a heavy-chain disease protein. Curr. Biol. 5, 1140–1148 8 Gething, M.J. (1999) Role and regulation of the ER chaperone BiP. Semin. Cell Dev. Biol. 10, 465–472 9 Minegishi, Y. and Conley, M.E. (2001) Negative selection at the preBCR checkpoint elicited by human mu heavy chains with unusual CDR3 regions. Immunity 14, 631–641 10 Su, Y.W. et al. (2003) Identification of a pre-BCR lacking surrogate light chain. J. Exp. Med. 198, 1699–1706 11 Schuh, W. et al. (2003) Cutting edge: signaling and cell surface expression of a mu H chain in the absence of lambda 5: a paradigm revisited. J. Immunol. 171, 3343–3347 12 Geraldes, P. et al. (2007) Ig heavy chain promotes mature B cell survival in the absence of light chain. J. Immunol. 179, 1659–1668 13 Corcos, D. et al. (2010) Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain. Blood 115, 282–288 0968-0004/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibs.2010.07.010 Trends in Biochemical Sciences, November 2010, Vol. 35, No. 11
Corresponding author: Corcos, D. ([email protected]).
593