Aggregates, Crystals, Gels, and Amyloids: Intracellular and Extracellular Phenotypes at the Crossroads of Immunoglobulin Physicochemical Property and Cell Physiology
Schematics of early secretory pathway compartments during recombinant IgG overexpression. (a) Increased efficiency in protein synthesis, translocation, and oxidative protein folding, in conjunction with limited capacities at the ER exit sites, can lead to a progressive accumulation of export-ready IgG in the ER lumen. VTC: vesicular tubular cluster. ERGIC: ER-Golgi intermediate compartment. (b) Upon reaching a critical threshold concentration, IgG crystals can form in the ER. Accumulated IgGs support the rapid growth of intra-ER crystals. Crystalline body formation in turn alleviates the crowding in the ER. Newly folded IgG will have two competing fates once the crystalline body phenotype is initiated. The first path is to become part of the growing crystals. The second path is to be packaged into COP II vesicles to exit the ER. After crystalline body is induced, many attempts to increase protein synthesis may not directly translate into a higher protein secretion output due to the two competing pathways.