Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, USA.
Nat Chem Biol. 2010 Jun;6(6):424-32. doi: 10.1038/nchembio.368. Epub 2010 May 9.
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.
已知改变细胞内钙离子水平可以部分恢复几种溶酶体贮积病中突变酶的体内平衡，但原因是什么呢？我们假设内质网（ER）钙离子增加可以通过增加伴侣蛋白的功能来增强这些易发生错误折叠和降解的突变溶酶体酶的折叠、运输和功能。在这里，我们报告说，通过使用拮抗剂或 RNAi 减少内质网钙流出，或者通过过表达 SERCA2b 促进内质网钙内流来增加内质网钙水平，可以增强来自戈谢病患者的细胞中突变葡萄糖脑苷脂酶（GC）的体内平衡。内质网钙离子浓度的升高对钙联蛋白折叠途径的翻译后调节似乎增强了该伴侣蛋白系统折叠突变易发生错误折叠的酶的能力，增加了可以与运输受体结合的折叠突变 GC 群体，而不是内质网相关降解，从而增加溶酶体 GC 的浓度和活性。
