PXD021444 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export |
Description | Cholesterol import in mammalian cells is mediated by the LDL receptor pathway. Here, we perform a genome-wide CRISPR screen using an endogenous cholesterol reporter and identify >100 genes involved in LDL-cholesterol import. We characterise C18orf8 as a core subunit of the mammalian Mon1-Ccz1 guanidine exchange factor (GEF) for Rab7, required for complex stability and function. C18orf8-deficient cells lack Rab7 activation and show severe defects in late endosome morphology and endosomal LDL trafficking, resulting in cellular cholesterol deficiency. Unexpectedly, free cholesterol accumulates within swollen lysosomes, suggesting a critical defect in lysosomal cholesterol export. We find that active Rab7 interacts with the NPC1 cholesterol transporter and licenses lysosomal cholesterol export. This process is abolished in C18orf8-, Ccz1- and Mon1A/B-deficient cells and restored by a constitutively active Rab7. The trimeric Mon1-Ccz1-C18orf8 (MCC) GEF therefore plays a central role in cellular cholesterol homeostasis coordinating Rab7 activation, endosomal LDL trafficking and NPC1-dependent lysosomal cholesterol export. |
HostingRepository | PRIDE |
AnnounceDate | 2020-10-29 |
AnnouncementXML | Submission_2020-11-09_04:41:56.xml |
DigitalObjectIdentifier | https://dx.doi.org/10.6019/PXD021444 |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Supported dataset by repository |
PrimarySubmitter | James Williamson |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Orbitrap Fusion |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2020-09-13 23:11:44 | ID requested | |
1 | 2020-10-29 06:22:13 | announced | |
⏵ 2 | 2020-11-09 04:41:57 | announced | 2020-11-09: Updated publication reference for PubMed record(s): 33144569. |
Publication List
van den Boomen DJH, Sienkiewicz A, Berlin I, Jongsma MLM, van Elsland DM, Luzio JP, Neefjes JJC, Lehner PJ, A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export. Nat Commun, 11(1):5559(2020) [pubmed] |
Keyword List
submitter keyword: C18orf8, Mon1, Ccz1, Rab7, GEF, LDL, cholesterol, NPC1, lysosome |
Contact List
Paul Lehner |
contact affiliation | Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, UK |
contact email | pjl30@cam.ac.uk |
lab head | |
James Williamson |
contact affiliation | University of Cambridge |
contact email | jcw76@cam.ac.uk |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD021444
- Label: PRIDE project
- Name: A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export