Endoplasmic reticulum Ca2+ increases enhance mutant glucocerebrosidase proteostasis
Open Access
- 9 May 2010
- journal article
- research article
- Published by Springer Nature in Nature Chemical Biology
- Vol. 6 (6), 424-432
- https://doi.org/10.1038/nchembio.368
Abstract
Enhancing calnexin function by increasing the ER calcium concentration resculpts the mutant glucocerebrosidase folding free energy diagram in the ER of Gaucher's disease cells, enhancing folding at the expense of the ER-associated degradation pathway. Altering intracellular calcium levels is known to partially restore mutant enzyme homeostasis in several lysosomal storage diseases, but why? We hypothesized that endoplasmic reticulum (ER) calcium increases enhance the folding, trafficking and function of these mutant misfolding- and degradation-prone lysosomal enzymes by increasing chaperone function. Here we report that increasing ER calcium levels by reducing ER calcium efflux through the ryanodine receptor, using antagonists or RNAi, or by promoting ER calcium influx by SERCA2b overexpression enhances mutant glucocerebrosidase (GC) homeostasis in cells derived from individuals with Gaucher's disease. Post-translational regulation of the calnexin folding pathway by an elevated ER calcium concentration seems 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 and activity.Keywords
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