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

In many protein storage diseases, detergent-insoluble proteins accumulate in the early secretory compartment (ESC). Protein condensation reflects imbalances between entry into (synthesis/translocation) and exit from (secretion/ degradation) ESC, and can be also a consequence of altered quality control (QC) mechanisms. Here we exploit the inducible formation of Russell bodies (RB), dilated ESC cisternae containing mutant Ig-μ chains, as a model to mechanistically dissect protein condensation. Depending on the presence or absence of Ig-L chains, mutant Ig-μ chains lacking their first constantdomain (CH1) accumulate in rough or smooth RB (rRB and sRB), dilations of the endoplasmic reticulum (ER) and ERGolgi intermediate compartment (ERGIC), respectively, reflecting the proximal and distal QC stations in the stepwise biogenesis of polymeric IgM. Either weakening ERp44-dependent distal QC or facilitating ER-associated degradation (ERAD) inhibits RB formation. Overexpression of PDI or ERp44 inhibits μ!CH1 secretion. However, PDI inhibits while ERp44 promotes μ!CH1 condensation. Both Ero1! silencing and overexpression prevent RB formation, demonstrating a strict redox dependency of the phenomenon. Altogether, our findings identify key controllers of protein condensation along the ESC as potential targets to handle certain storage disorders. Key words: early secretory compartment, endoplasmic reticulum, ERGIC, protein condensation