The association of lipid transfer protein VPS13A with endosomes is mediated by sorting nexin SNX5

Abstract

Human VPS13 proteins are implicated in severe neurological diseases. These proteins play an important role in lipid transport at membrane contact sites between different organelles. Identification of adaptors that regulate the subcellular localization of these proteins at specific membrane contact sites is essential to understand their function and role in disease. We have identified the sorting nexin SNX5 as an interactor of VPS13A that mediates its association with endosomal subdomains. As for the yeast sorting nexin and Vps13 endosomal adaptor Ypt35, this association involves the VPS13 adaptor-binding (VAB) domain in VPS13A and a PxP motif in SNX5. Notably, this interaction is impaired by mutation of a conserved asparagine residue in the VAB domain, which is also required for Vps13-adaptor binding in yeast and is pathogenic in VPS13D. VPS13A fragments containing the VAB domain co-localize with SNX5, whereas the more C-terminal part of VPS13A directs its localization to the mitochondria. Overall, our results suggest that a fraction of VPS13A localizes to junctions between the endoplasmic reticulum, mitochondria, and SNX5-containing endosomes.

RBG Motif Bridge-Like Lipid Transport Proteins: Structure, Functions, and Open Questions

“…VPS13A is localized at contacts of the ER with mitochondria and with the plasma membrane (PM) via competitive interactions of its C-terminal PH domain with either a still unknown binding site on mitochondria (Kumar et al 2018) or the PM-localized lipid scramblase XK (Guillén-Samander et al 2022, Park & Neiman 2020, Park et al 2022, Ryoden et al 2022, Urata et al 2019. A localization of VPS13A at contacts between the ER and endosomes mediated by its VAB domain and the retromer component SNX5 has also been recently reported (Tornero-Écija et al 2023). The interaction with XK is likely to be especially important as LoF mutations in either VPS13A or XK result in two rare and very similar clinical conditions: chorea-acanthocytosis (Rampoldi et al 2001, Ueno et al 2001) (VPS13 mutation) and McLeod syndrome (Ho et al 1994) (XK mutations).…”

Bridge-Like Lipid Transfer Proteins (BLTPs) in C. elegans: From Genetics to Structures and Functions

“…By contrast, RNAi against T08G11.1 does not appear to cause any apparent phenotypes in C. elegans. As mammalian VPS13D and VPS13A can localize to mitochondria-endosomes and mitochondria-ER (Guillén-Samander et al, 2021;Tornero-Écija et al, 2023), it remains to be investigated whether C. elegans counterparts also localize to these organelles to mediate lipid transport.…”