VPS13A and VPS13C are lipid transport proteins differentially localized at ER contact sites

• Published in: The Journal of cell biology Vol. 217; no. 10; pp. 3625 - 3639
• Main Authors: Kumar, Nikit, Leonzino, Marianna, Hancock-Cerutti, William, Horenkamp, Florian A., Li, PeiQi, Lees, Joshua A., Wheeler, Heather, Reinisch, Karin M., De Camilli, Pietro
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01.10.2018
• Subjects: Animals; Autophagy; Autophagy-Related Proteins - genetics; Autophagy-Related Proteins - metabolism; Chlorocebus aethiops; Chorea; COS Cells; Disorders; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - metabolism; Endosomes - genetics; Endosomes - metabolism; HeLa Cells; Homeostasis; Human behavior; Humans; Hydrophobicity; Lipid Droplets - metabolism; Lipids; Lysosomes; Lysosomes - genetics; Lysosomes - metabolism; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mutation; Neurodegeneration; Neurodegenerative diseases; Neurodevelopmental disorders; Neurological diseases; Organelles; Parkinson's disease; Phagocytosis; Protein Domains; Protein structure; Protein Structure, Secondary; Protein transport; Proteins; Proteins - genetics; Proteins - metabolism; Saccharomyces cerevisiae; Secondary structure; Tethering; Transport; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism; Yeast
• ISSN: 0021-9525; 1540-8140; 1540-8140
• DOI: 10.1083/jcb.201807019

Mutations in the human VPS13 genes are responsible for neurodevelopmental and neurodegenerative disorders including chorea acanthocytosis (VPS13A) and Parkinson’s disease (VPS13C). The mechanisms of these diseases are unknown. Genetic studies in yeast hinted that Vps13 may have a role in lipid exchange between organelles. In this study, we show that the N-terminal portion of VPS13 is tubular, with a hydrophobic cavity that can solubilize and transport glycerolipids between membranes. We also show that human VPS13A and VPS13C bind to the ER, tethering it to mitochondria (VPS13A), to late endosome/lysosomes (VPS13C), and to lipid droplets (both VPS13A and VPS13C). These findings identify VPS13 as a lipid transporter between the ER and other organelles, implicating defects in membrane lipid homeostasis in neurological disorders resulting from their mutations. Sequence and secondary structure similarity between the N-terminal portions of Vps13 and other proteins such as the autophagy protein ATG2 suggest lipid transport roles for these proteins as well.