A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export.

Szczegóły
Abstrakt

Tytuł:: A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export.
Autorzy:: van den Boomen DJH; Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK. .
Sienkiewicz A; Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK.
Berlin I; Leiden University Medical Centre, Leiden University, Leiden, The Netherlands.
Jongsma MLM; Leiden University Medical Centre, Leiden University, Leiden, The Netherlands.
van Elsland DM; Leiden University Medical Centre, Leiden University, Leiden, The Netherlands.
Luzio JP; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
Neefjes JJC; Leiden University Medical Centre, Leiden University, Leiden, The Netherlands.
Lehner PJ; Cambridge Institute of Therapeutic Immunology & Infectious Disease, University of Cambridge, Cambridge, UK. .
Źródło:: Nature communications [Nat Commun] 2020 Nov 03; Vol. 11 (1), pp. 5559. Date of Electronic Publication: 2020 Nov 03.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: [London] : Nature Pub. Group
MeSH Terms:: Protein Multimerization*
Cholesterol/*metabolism
Intracellular Signaling Peptides and Proteins/*metabolism
Lysosomes/*metabolism
rab GTP-Binding Proteins/*metabolism
Biological Transport ; CRISPR-Cas Systems/genetics ; Cholesterol, LDL/metabolism ; Endosomes/metabolism ; Endosomes/ultrastructure ; Fluorescent Dyes/metabolism ; Genome, Human ; Guanine Nucleotide Exchange Factors/metabolism ; HEK293 Cells ; HeLa Cells ; Homeostasis ; Humans ; Hydroxymethylglutaryl-CoA Synthase/metabolism ; Lysosomes/ultrastructure ; Models, Biological ; Multiprotein Complexes/metabolism ; Niemann-Pick C1 Protein ; Protein Binding ; rab7 GTP-Binding Proteins
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Grant Information:: 084957/Z/08/Z United Kingdom WT_ Wellcome Trust; MR/R009015/1 United Kingdom MRC_ Medical Research Council; United Kingdom WT_ Wellcome Trust; 100140 United Kingdom WT_ Wellcome Trust; 210688/Z/18/Z United Kingdom WT_ Wellcome Trust; MR/R0009015/1 United Kingdom MRC_ Medical Research Council
Substance Nomenclature:: 0 (Cholesterol, LDL)
0 (Fluorescent Dyes)
0 (Guanine Nucleotide Exchange Factors)
0 (Intracellular Signaling Peptides and Proteins)
0 (Multiprotein Complexes)
0 (NPC1 protein, human)
0 (Niemann-Pick C1 Protein)
0 (rab7 GTP-Binding Proteins)
0 (rab7 GTP-binding proteins, human)
97C5T2UQ7J (Cholesterol)
EC 2.3.3.10 (HMGCS1 protein, human)
EC 2.3.3.10 (Hydroxymethylglutaryl-CoA Synthase)
EC 3.6.5.2 (rab GTP-Binding Proteins)
Entry Date(s):: Date Created: 20201104 Date Completed: 20201124 Latest Revision: 20230726
Update Code:: 20240105
PubMed Central ID:: PMC7642327
DOI:: 10.1038/s41467-020-19032-0
PMID:: 33144569
: Czasopismo naukowe

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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.

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