title: Endoplasmic reticulum Ca2+ increases enhance mutant glucocerebrosidase proteostasis.
abstract: 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.
authors.affiliation: Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Derrick Sek Tong
authors.initials: DS
authors.lastname: Ong
authors.forename: Ting-Wei
authors.initials: TW
authors.lastname: Mu
authors.forename: Amy E
authors.initials: AE
authors.lastname: Palmer
authors.forename: Jeffery W
authors.initials: JW
authors.lastname: Kelly
mesh_terms: D019943:Amino Acid Substitution; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004110:Diltiazem / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D005776:Gaucher Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D017510:Protein Folding / Q000187:drug effects; D011499:Protein Processing, Post-Translational; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; D014665:Vasodilator Agents; D014700:Verapamil; D005962:Glucosylceramidase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D004110:Diltiazem; D002118:Calcium
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