ERp44 and ERGIC-53 synergize in coupling efficiency and fidelity of IgM polymerization and secretion

Owing to the quality control mechanisms operating in the early secretory compartment, only native proteins are secreted. Despite the difficulties in assembling planar immunoglobulin M (IgM) polymers, antibody-secreting cells can release up to thousands of IgM per second. The finding that secretory μ (μ_s) chains bind to ERGIC-53, a lectin transporter that cycles in the early secretory compartment, suggested that ERGIC-53 hexamers could provide a polymerization platform. Here, we show that ERGIC-53 binds to the conserved Asn563 glycan in the C-terminal μ_s tailpiece (μ_stp). Removal of this glycan inhibits ERGIC-53 binding and results in the rapid formation of larger polymeric assemblies. In contrast, removal of the Asn402 oligosaccharides prevents both polymerization and secretion. ERp44, a chaperone that interacts with ERGIC-53, binds to Cys575 in the μ_stp, providing a fail-safe mechanism that retrieves unpolymerized IgM subunits and promotes polymerization. The coordinated action of ERGIC-53 and ERp44 provides a way to improve the efficiency of IgM secretion without perturbing its fidelity.