NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C.
NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C.
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DOI：
10.1016/j.devcel.2020.11.016
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发表时间：
2021-02-08
影响因子：
11.8
通讯作者：
Zoncu R
中科院分区：
文献类型：
--
作者：
Davis OB;Shin HR;Lim CY;Wu EY;Kukurugya M;Maher CF;Perera RM;Ordonez MP;Zoncu R
溶酶体通过其管腔内的大分子水解酶和其限制膜上的mTORC1激酶的代谢信号来促进细胞的动态平衡。水解性和信号转导功能都需要对溶酶体胆固醇含量的精确调控。在Niemann-Pick C型(NPC)中，胆固醇输出蛋白NPC1的缺失会导致胆固醇在溶酶体内积聚，导致mTORC1过度激活，线粒体功能障碍和神经变性。鼻咽癌溶酶体的组成和功能变化，以及异常的胆固醇-mTORC1信号如何在细胞器发病中起作用尚不清楚。通过对鼻咽癌溶酶体的蛋白质组学分析，我们发现明显的蛋白水解性损伤伴随着水解酶耗竭、膜损伤和有丝分裂缺陷。遗传和药物上的mTORC1抑制可以在不纠正胆固醇储存的情况下恢复溶酶体的蛋白分解，暗示异常的mTORC1是胆固醇积累下游的致病驱动因素。在鼻咽癌神经元模型中，mTORC1抑制一贯地改善线粒体功能障碍。因此，胆固醇-mTORC1信号控制细胞器的动态平衡，是鼻咽癌的靶向通路。Niemann-Pick C型是一种由溶酶体中胆固醇积聚引起的破坏性神经退行性疾病。通过细胞器蛋白质组学，Davis等发现了鼻咽癌溶酶体的降解缺陷和结构缺陷。异常的mTORC1信号导致胆固醇积累下游的溶酶体功能障碍，化学和遗传的mTORC1抑制可以恢复鼻咽癌细胞中细胞器的动态平衡。
Lysosomes promote cellular homeostasis through macromolecular hydrolysis within their lumen and metabolic signaling by the mTORC1 kinase on their limiting membranes. Both hydrolytic and signaling functions require precise regulation of lysosomal cholesterol content. In Niemann-Pick type C (NPC), loss of the cholesterol exporter, NPC1, causes cholesterol accumulation within lysosomes, leading to mTORC1 hyperactivation, disrupted mitochondrial function and neurodegeneration. The compositional and functional alterations in NPC lysosomes, and how aberrant cholesterol-mTORC1 signaling contributes to organelle pathogenesis are not understood. Through proteomic profiling of NPC lysosomes, we find pronounced proteolytic impairment compounded with hydrolase depletion, enhanced membrane damage and defective mitophagy. Genetic and pharmacologic mTORC1 inhibition restores lysosomal proteolysis without correcting cholesterol storage, implicating aberrant mTORC1 as a pathogenic driver downstream of cholesterol accumulation. Consistently, mTORC1 inhibition ameliorates mitochondrial dysfunction in a neuronal model of NPC. Thus, cholesterol-mTORC1 signaling controls organelle homeostasis and is a targetable pathway in NPC. Niemann-Pick type C is a devastating neurodegenerative disease caused by cholesterol buildup in lysosomes. Through organelle proteomics, Davis et al identify degradative and structural defects of NPC lysosomes. Aberrant mTORC1 signaling drives lysosomal dysfunction downstream of cholesterol accumulation, and chemical and genetic mTORC1 inhibition restores organelle homeostasis in NPC cells.
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影响因子：
64.8
作者：
Israel, Mason A.;Yuan, Shauna H.;Bardy, Cedric;Reyna, Sol M.;Mu, Yangling;Herrera, Cheryl;Hefferan, Michael P.;Van Gorp, Sebastiaan;Nazor, Kristopher L.;Boscolo, Francesca S.;Carson, Christian T.;Laurent, Louise C.;Marsala, Martin;Gage, Fred H.;Remes, Anne M.;Koo, Edward H.;Goldstein, Lawrence S. B.
通讯作者：
Goldstein, Lawrence S. B.
影响因子：
3.5
作者：
Chung, Chan;Puthanveetil, Prasanth;Lieberman, Andrew P.
通讯作者：
Lieberman, Andrew P.
影响因子：
6.5
作者：
Feltes, McKenna;Gale, Sarah E.;Schaffer, Jean E.
通讯作者：
Schaffer, Jean E.
DOI：
10.1126/science.aag1417
发表时间：
2017-03-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Castellano BM;Thelen AM;Moldavski O;Feltes M;van der Welle RE;Mydock-McGrane L;Jiang X;van Eijkeren RJ;Davis OB;Louie SM;Perera RM;Covey DF;Nomura DK;Ory DS;Zoncu R
通讯作者：
Zoncu R
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere