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Comparative proximity biotinylation implicates RAB18 in cholesterol mobilization and biosynthesis

By Robert S Kiss, Jarred Chicoine, Youssef Khalil, Robert Sladek, He Chen, Alessandro Pisaturo, Cyril Martin, Jessica D Dale, Tegan A Brudenell, Archith Kamath, Emanuele Paci, Peter Clayton, Jimi C Wills, Alex von Kriegsheim, Tommy Nilsson, Eamonn Sheridan, Mark T Handley

Posted 10 Dec 2019
bioRxiv DOI: 10.1101/871517

Loss of functional RAB18 causes the autosomal recessive condition Warburg Micro syndrome. To better understand this disease, we used proximity biotinylation to generate an inventory of potential RAB18 effectors. A restricted set of 25 RAB18-interactions were dependent on the binary RAB3GAP1-RAB3GAP2 RAB18-guanine nucleotide exchange factor (GEF) complex. Consistent with a role for RAB18 in regulating membrane contact sites (MCSs), interactors included groups of microtubule/membrane-remodelling proteins, membrane-tethering and docking proteins, and lipid-modifying/transporting proteins. We provide evidence validating novel interactions with SEC22A and TMCO4. We also provide functional evidence that RAB18 links the {Delta}8-{Delta}7 sterol isomerase emopamil binding protein (EBP) to a molecular machinery mobilizing the products of EBP-catalysis. The cholesterol precursor lathosterol accumulates in RAB18-null cells, and de novo cholesterol biosynthesis is reduced. Our data demonstrate that GEF-dependent Rab-interactions are highly amenable to interrogation by proximity biotinylation and suggest that Micro syndrome is a cholesterol biosynthesis disorder.

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