Endoplasmic Reticulum Ca(2+) Increases Enhance Mutant Glucocerebrosidase Proteostasis

Altering intracellular calcium levels is known to partially restore mutant enzyme homeostasis in several lysosomal storage diseases, but why? We hypothesize that endoplasmic reticulum (ER) calcium level increases enhance the folding, trafficking and function of these mutant misfolding/degradation-prone lysosomal enzymes by increasing chaperone function. Herein, we report that increasing ER calcium levels by reducing ER calcium efflux through the ryanodine receptor (antagonists or RNAi) or by promoting ER calcium influx by SERCA2b overexpression enhances mutant glucocerebrosidase (GC) homeostasis in Gaucher’s disease patient-derived cells. Post-translational regulation of the calnexin folding pathway by increasing the ER calcium concentration appears to enhance the capacity of this chaperone system to fold mutant misfolding-prone enzymes, increasing the folded mutant GC population that can engage the trafficking receptor at the expense of ER-associated degradation, increasing the lysosomal GC concentration.