دورية أكاديمية
أعرض في EDS

ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann-Pick type C.

التفاصيل البيبلوغرافية
العنوان: ER-lysosome contacts enable cholesterol sensing by mTORC1 and drive aberrant growth signalling in Niemann-Pick type C.
المؤلفون: Lim CY; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA, USA., Davis OB; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA, USA., Shin HR; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA, USA., Zhang J; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA, USA., Berdan CA; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA., Jiang X; Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, USA., Counihan JL; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA., Ory DS; Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, USA., Nomura DK; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.; Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA, USA., Zoncu R; Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA. rzoncu@berkeley.edu.; The Paul F. Glenn Center for Aging Research, University of California, Berkeley, Berkeley, CA, USA. rzoncu@berkeley.edu.
المصدر: Nature cell biology [Nat Cell Biol] 2019 Oct; Vol. 21 (10), pp. 1206-1218. Date of Electronic Publication: 2019 Sep 23.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Macmillan Magazines Ltd Country of Publication: England NLM ID: 100890575 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4679 (Electronic) Linking ISSN: 14657392 NLM ISO Abbreviation: Nat Cell Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Macmillan Magazines Ltd., [1999-
مواضيع طبية MeSH: Cholesterol/*metabolism , Endoplasmic Reticulum/*metabolism , Lysosomes/*metabolism , Mechanistic Target of Rapamycin Complex 1/*metabolism , Niemann-Pick Diseases/*metabolism , Receptors, Steroid/*metabolism, Animals ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; HEK293 Cells ; Humans ; Intracellular Signaling Peptides and Proteins ; Mechanistic Target of Rapamycin Complex 1/genetics ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Mice ; Niemann-Pick C1 Protein ; Receptors, Steroid/genetics ; Signal Transduction ; Vesicular Transport Proteins/genetics ; Vesicular Transport Proteins/metabolism
مستخلص: Cholesterol activates the master growth regulator, mTORC1 kinase, by promoting its recruitment to the surface of lysosomes by the Rag guanosine triphosphatases (GTPases). The mechanisms that regulate lysosomal cholesterol content to enable mTORC1 signalling are unknown. Here, we show that oxysterol binding protein (OSBP) and its anchors at the endoplasmic reticulum (ER), VAPA and VAPB, deliver cholesterol across ER-lysosome contacts to activate mTORC1. In cells lacking OSBP, but not other VAP-interacting cholesterol carriers, the recruitment of mTORC1 by the Rag GTPases is inhibited owing to impaired transport of cholesterol to lysosomes. By contrast, OSBP-mediated cholesterol trafficking drives constitutive mTORC1 activation in a disease model caused by the loss of the lysosomal cholesterol transporter, Niemann-Pick C1 (NPC1). Chemical and genetic inactivation of OSBP suppresses aberrant mTORC1 signalling and restores autophagic function in cellular models of Niemann-Pick type C (NPC). Thus, ER-lysosome contacts are signalling hubs that enable cholesterol sensing by mTORC1, and targeting the sterol-transfer activity of these signalling hubs could be beneficial in patients with NPC.
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معلومات مُعتمدة: DP2 CA195761 United States CA NCI NIH HHS; P30 DK056341 United States DK NIDDK NIH HHS; R01 GM127763 United States GM NIGMS NIH HHS; R01 HL067773 United States HL NHLBI NIH HHS
المشرفين على المادة: 0 (Carrier Proteins)
0 (Intracellular Signaling Peptides and Proteins)
0 (Membrane Glycoproteins)
0 (NPC1 protein, human)
0 (Niemann-Pick C1 Protein)
0 (Receptors, Steroid)
0 (VAPA protein, human)
0 (VAPB protein, human)
0 (Vesicular Transport Proteins)
0 (oxysterol binding protein)
97C5T2UQ7J (Cholesterol)
EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
تواريخ الأحداث: Date Created: 20190925 Date Completed: 20191125 Latest Revision: 20220726
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6936960
DOI: 10.1038/s41556-019-0391-5
PMID: 31548609
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-4679
DOI:10.1038/s41556-019-0391-5