Sequential steps and checkpoints in the early exocytic compartment during secretory IgM biogenesis

The biogenesis of secretory IgM occurs stepwise under stringent quality control, formation of mu L-2(2) preceding polymerization. How is efficiency of IgM secretion coupled to fidelity? We show here that ERp44, a soluble protein involved in thiol-mediated retention, interacts with ERGIC-53. Binding to this hexameric lectin contributes to ERp44 localization in the ER-golgi intermediate compartment. ERp44 and ERGIC-53 increase during B-lymphocyte differentiation, concomitantly with the onset of IgM polymerization. Both preferentially bind mu L-2(2) and higher order intermediates. Their overexpression or silencing in non-lymphoid cells promotes or decreases secretion of IgM polymers, respectively. In IgM-secreting B-lymphoma cells, l chains interact first with BiP and later with ERp44 and ERGIC-53. Our findings suggest that ERGIC53 provides a platform that receives mu L-2(2) subunits from the BiP-dependent checkpoint, assisting polymerization. In this process, ERp44 couples thiol-dependent assembly and quality control.