Cooperative control of IgA synthesis and secretion by MZB1 and the J chain

Immunoglobulin A (IgA) is the most abundantly produced antibody in mammals, with its secretory dimeric form playing a central role in maintaining intestinal homeostasis. Although the J chain is known to be essential for IgA transcytosis, its precise role in IgA biosynthesis and secretion is not fully understood. Here, using CRISPR/Cas9-edited J558 plasmacytoma cells, a mouse line that secretes IgA, we demonstrate that MZB1 and the J chain act sequentially to ensure proper IgA assembly. MZB1 stabilizes α-heavy chain-light chain complexes (HL complexes), thereby enabling their efficient association with the J chain, which subsequently drives rapid assembly into IgA dimers and higher-order polymers. Loss of MZB1 reduced the secretion of dimeric IgA, whereas J chain deficiency caused both excessive intracellular accumulation and secretion of HL complexes, while allowing the generation and secretion of limited amounts of monomeric IgA but completely abolishing dimer formation. Combined deficiency reproduced the additive defects of the single knockouts, confirming their cooperative function in a shared assembly pathway. In vivo, loss of MZB1, the J chain, or both altered IgA abundance and form, differentially affected susceptibility to DSS-induced colitis, and reshaped gut microbiota composition. These findings define a cooperative mechanism by which MZB1 and the J chain orchestrate IgA biogenesis, with MZB1 regulating quantity and the J chain determining quality, and reveal how variation in IgA form and abundance contributes to mucosal immune protection.