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 l2L2 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 l2L2 and higher order intermediates. Their overexpression or silencing in nonlymphoid 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 ERGIC- 53 provides a platform that receives l2L2 subunits from the BiP-dependent checkpoint, assisting polymerization. In this process, ERp44 couples thiol-dependent assembly and quality control.