ER storage diseases: a role for ERGIC-53 in controlling the formation and shape of Russell bodies.

Owing to the impossibility of reaching the Golgi for secretion or the cytosol fordegradation, mutant Ig-mu chains that lack the first constant domain (muDeltaCH1)accumulate as detergent-insoluble aggregates in dilated endoplasmic reticulumcisternae, called Russell bodies. The presence of similar structures hallmarksmany ER storage diseases, but their pathogenic role(s) remain obscure. Exploitinginducible cellular systems, we show here that Russell bodies form when thesynthesis of muDeltaCH1 exceeds the degradation capacity. Condensation occurs in different sub-cellular locations, depending on the interacting molecules present in the host cell: if Ig light chains are co-expressed, detergent-insolublemuDeltaCH1-light chain oligomers accumulate in large ribosome-coated structures(rough Russell bodies). In absence of light chains, instead, aggregation occursin smooth tubular vesicles and is controlled by N-glycan-dependent interactionswith ER-Golgi intermediate compartment 53 (ERGIC-53). In cells containing smooth Russell bodies, ERGIC-53 co-localizes with muDeltaCH1 aggregates in a Ca2+-dependent fashion. Our findings identify a novel ERGIC-53 substrate, andindicate that interactions with light chains or ERGIC-53 seed muDeltaCH1condensation in different stations of the early secretory pathway.