Abstract
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.
Highlights
In the arms race between pathogens and hosts, vertebrates developed a long-range weapon of high precision: the antibody
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
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
Summary
In the arms race between pathogens and hosts, vertebrates developed a long-range weapon of high precision: the antibody. In place of a transmembrane domain, the C terminus of Ig-μs HC displays a hydrophilic tail piece (TP) with one cysteine that is key both for preventing premature secretion and for the assembly of mature secretory IgM (see below). Once it commits to the plasma cell stage, the TP cysteine is used, to covalently link H2L2 “monomeric” units in polymeric secretory IgM by disulfide bonds [2]. Plasma cells secrete IgM either as “hexamers” (H2L2) or as “pentamers” (H2L2)5J, in which a third antibody component, the J-chain, joins the “monomeric” units, again by disulfide bonds [1]. Secretory IgM consists of entities that each exceeds 1 megadalton in molecular weight, as they are composed in the “pentameric” state of 21 polypeptides, bearing in total 51 N-glycans, and containing 98 intrachain and interchain disulfide bonds [1] (Figure 1)
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