The efficiency of cysteine-mediated intracellular retention determines the differential fate of secretory IgA and IgM in B and plasma cells.
Previous studies on IgM secretion demonstrated a role for the mu chain C-terminal cysteine (Cys575) in preventing the transport of unpolymerized subunits along the secretory pathway. The sequence homology between the C-terminal tailpieces of mu and alpha heavy chains prompted us to investigate the role of cysteine-mediated, retention in the control of IgA secretion during B cell development. Similar to IgM, IgA are not secreted by B lymphocytes: the retention mechanism can be reversed by the reducing agent 2-mercaptoethanol, suggesting that disulfide interchange reactions are involved in the quality control of both IgM and IgA. Yet, alpha 2L2 subunits, but not mu2L2, are secreted constitutively by plasma cells. We demonstrate that the differential retention of IgM and IgA subunits by myeloma transfectants is mainly due to the presence of an acidic residue upstream the alpha chain C-terminal cysteine. The regulation of polymeric Ig secretion during B cell development provides an example of how thiol-mediated quality control can be modulated according to the aminoacidic context surrounding the critical cysteine and to the cell type.
Guenzi
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DIBIT-San Raffaele Scientific Institute, Milano, Italy.
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Sparvoli
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Rocco
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D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D001483:Base Sequence; D001692:Biological Transport; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry; D017931:DNA Primers / Q000737:chemistry; D007070:Immunoglobulin A / Q000378:metabolism; D007071:Immunoglobulin A, Secretory / Q000737:chemistry / Q000378:metabolism*; D007075:Immunoglobulin M / Q000737:chemistry / Q000378:metabolism*; D007137:Immunoglobulin alpha-Chains / Q000737:chemistry; D007148:Immunoglobulin mu-Chains / Q000737:chemistry; D066298:In Vitro Techniques; D051379:Mice; D008969:Molecular Sequence Data; D010950:Plasma Cells / Q000378:metabolism*; D012636:Secretory Rate; D013329:Structure-Activity Relationship
D017931:DNA Primers; D007070:Immunoglobulin A; D007071:Immunoglobulin A, Secretory; D007075:Immunoglobulin M; D007137:Immunoglobulin alpha-Chains; D007148:Immunoglobulin mu-Chains; C034639:polymeric IgA; C024242:polymeric IgM; D003545:Cysteine