Pathogenesis of ER Storage Disorders: Modulating Russell Body Biogenesis by Altering Proximal and Distal Quality Control

In many protein storage diseases, detergent-insolubleproteins accumulate in the early secretory compartment(ESC). Protein condensation reflects imbalances betweenentry into (synthesis/translocation) and exit from (secre-tion/degradation) ESC, and can be also a consequenceof altered quality control (QC) mechanisms. Here weexploit the inducible formation of Russell bodies (RB),dilated ESC cisternae containing mutant Ig-μchains,as a model to mechanistically dissect protein conden-sation. Depending on the presence or absence of Ig-Lchains, mutant Ig-μchains lacking their first constantdomain (CH1) accumulate in rough or smooth RB (rRB andsRB), dilations of the endoplasmic reticulum (ER) and ER-Golgi intermediate compartment (ERGIC), respectively,reflecting the proximal and distal QC stations in thestepwise biogenesis of polymeric IgM. Either weakeningERp44-dependent distal QC or facilitating ER-associateddegradation (ERAD) inhibits RB formation. Overexpres-sion of PDI or ERp44 inhibitsμ CH1 secretion. However,PDI inhibits while ERp44 promotesμ CH1 condensa-tion. Both Ero1αsilencing and overexpression preventRB formation, demonstrating a strict redox dependencyof the phenomenon. Altogether, our findings identify keycontrollers of protein condensation along the ESC aspotential targets to handle certain storage disorders