HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts.
HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts.
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DOI：
10.1016/j.jlr.2021.100114
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发表时间：
2021
影响因子：
6.5
通讯作者：
Maxfield FR
中科院分区：
文献类型：
--
作者：
Pipalia NH;Saad SZ;Subramanian K;Cross A;Al-Motawa A;Garg K;Blagg BSJ;Neckers L;Helquist P;Wiest O;Ory DS;Maxfield FR
尼曼-皮克C1型（NPC 1）病是一种由NPC 1基因突变引起的溶酶体脂质储存障碍。在患者中报告了超过300种疾病相关突变，导致许多细胞类型的晚期内体和溶酶体（LE/Ly）中未酯化胆固醇、鞘糖脂和其他脂质的异常积累。以前，我们表明，许多不同的NPC 1突变成纤维细胞与组蛋白脱乙酰酶抑制剂的治疗导致胆固醇储存减少，我们发现，这是与增强出口的NPC 1蛋白质从内质网和交付LE/赖氨酸。这表明组蛋白去乙酰化酶抑制剂可能通过蛋白伴侣的变化来增强NPC 1突变体的折叠，从而使它们被递送到LE/Ly。在这项研究中，我们评估了几种HSP 90抑制剂对NPC 1 I1061 T皮肤成纤维细胞的影响。我们发现HSP 90抑制导致LE/Ly中胆固醇的清除，这与突变NPC 1 I1061 T蛋白向LE/Ly的递送增强有关。我们还观察到，抑制HSP 90增加HSP 70的表达，并且HSP 70的过表达也降低了NPC 1 I1061 T成纤维细胞中的胆固醇储存。然而，我们没有看到arimoclomol（一种据报道可以增加HSP 70表达的药物）在剂量高达0.5 mM时对胆固醇储存的纠正。作为HSP 90的结果，其他分子伴侣的增加改善了NPC 1蛋白的折叠，并减轻了NPC 1突变成纤维细胞中的胆固醇积累。
Niemann-Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of the NPC1 gene. More than 300 disease-associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids, and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many different NPC1 mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work through changes in protein chaperones to enhance the folding of NPC1 mutants, allowing them to be delivered to LE/Ly. In this study, we evaluated the effect of several HSP90 inhibitors on NPC1I1061T skin fibroblasts. We found that HSP90 inhibition resulted in clearance of cholesterol from LE/Ly, and this was associated with enhanced delivery of the mutant NPC1I1061T protein to LE/Ly. We also observed that inhibition of HSP90 increased the expression of HSP70, and overexpression of HSP70 also reduced cholesterol storage in NPC1I1061T fibroblasts. However, we did not see correction of cholesterol storage by arimoclomol, a drug that is reported to increase HSP70 expression, at doses up to 0.5 mM. The increase in other chaperones as a consequence of HSP90 improves folding of NPC1 protein and relieves cholesterol accumulation in NPC1 mutant fibroblasts.
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DOI：
10.1002/chem.201703398
发表时间：
2017-11-07
期刊：
Chemistry (Weinheim an der Bergstrasse, Germany)
影响因子：
--
作者：
Crowley VM;Huard DJE;Lieberman RL;Blagg BSJ
通讯作者：
Blagg BSJ
影响因子：
9.8
作者：
Greer, WL;Dobson, MJ;Neumann, PE
通讯作者：
Neumann, PE
DOI：
10.1158/1078-0432.ccr-16-3151
发表时间：
2017-10-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Canella A;Welker AM;Yoo JY;Xu J;Abas FS;Kesanakurti D;Nagarajan P;Beattie CE;Sulman EP;Liu J;Gumin J;Lang FF;Gurcan MN;Kaur B;Sampath D;Puduvalli VK
通讯作者：
Puduvalli VK
影响因子：
6
作者：
Farmer, Cristan A.;Thurm, Audrey;Porter, Forbes D.
通讯作者：
Porter, Forbes D.
影响因子：
4.8
作者：
Baldo, Barbara;Weiss, Andreas;Kaupmann, Klemens
通讯作者：
Kaupmann, Klemens