A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export

Dick J. H. Boomen (), Agata Sienkiewicz, Ilana Berlin, Marlieke L. M. Jongsma, Daphne M. Elsland, J. Paul Luzio, Jacques J. C. Neefjes and Paul J. Lehner ()
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Dick J. H. Boomen: University of Cambridge
Agata Sienkiewicz: University of Cambridge
Ilana Berlin: Leiden University
Marlieke L. M. Jongsma: Leiden University
Daphne M. Elsland: Leiden University
J. Paul Luzio: University of Cambridge
Jacques J. C. Neefjes: Leiden University
Paul J. Lehner: University of Cambridge

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19032-0

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