Comparative proximity biotinylation implicates the small GTPase RAB18 in sterol mobilization and biosynthesis

Kiss, Robert S.; Chicoine, Jarred; Khalil, Youssef; Sladek, Robert; Chen, He; Pisaturo, Alessandro; Martin, Cyril; Dale, Jessica D.; Brudenell, Tegan A.; Kamath, Archith; Kyei-Boahen, Jeffrey; Hafiane, Anouar; Daliah, Girija; Alecki, Célia; Hopes, Tayah S.; Heier, Martin; Aligianis, Irene A.; Lebrun, Jean-Jacques; Aspden, Julie; Paci, Emanuele; Kerksiek, Anja; Lütjohann, Dieter; Clayton, Peter; Wills, Jimi C.; von Kriegsheim, Alex; Nilsson, Tommy; Sheridan, Eamonn; Handley, Mark T.

doi:10.1016/j.jbc.2023.105295

Cited by 4 publications

(1 citation statement)

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“…The complexes attach to intracellular membranes via binding to specific membrane-anchored Rab proteins, for which they have an activating guanine nucleotide exchange factor (GEF) function. The TrappII complex preferentially interacts with Rab11, Rab18, Rab19 and Rab43, but has also GEF activity for Rab1, which is however regarded as the main substrate for TrappIII (Galindo & Munro, 2023; Jenkins et al, 2020; Ke et al, 2020; Kiss et al, 2023; Li et al, 2017). Rab11 regulates endosome recycling and Trappc9-deficient neurons show a delay in recycling of the transferrin receptor (Ke et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Microcephaly with a disproportionate hippocampal reduction, stem cell loss and neuronal lipid droplet symptoms inTrappc9KO mice

Aljuraysi,

Platt,

Pulix

et al. 2023

Preprint

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Mutations of the humanTRAFFICKING PROTEIN PARTICLE COMPLEX SUBUNIT 9(TRAPPC9) cause a neurodevelopmental disorder characterised by microcephaly and intellectual disability. Trappc9 constitutes a subunit specific to the intracellular membrane-associated TrappII complex. The TrappII complex interacts with Rab11 and Rab18, the latter being specifically associated with lipid droplets (LDs). Here we used non-invasive imaging to characteriseTrappc9knock-out (KO) mice as a model of the human hereditary disorder. KOs developed postnatal microcephaly with many grey and white matter regions being affected.In vivoMRI identified a disproportionately stronger volume reduction in the hippocampus, which was associated with a significant loss of Sox2-positive neural stem and progenitor cells. Diffusion Tensor imaging indicated a reduced organisation or integrity of white matter areas.Trappc9KOs displayed behavioural abnormalities in several tests related to exploration, learning and memory. Trappc9-deficient primary hippocampal neurons accumulated a larger LD volume per cell following Oleic Acid stimulation, and the coating of LDs by Perilipin-2 was much reduced. Additionally,Trappc9KOs developed obesity, which was significantly more severe in females than in males. Our findings indicate that, beyond previously reported Rab11-related vesicle transport defects, dysfunctions in LD homeostasis might contribute to the neurobiological symptoms of Trappc9 deficiency.

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