期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：35
DOI：10.1073/pnas.2205425119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Chorea-acanthocytosis and McLeod syndrome, due to mutations in VPS13A and XK, respectively, share similar manifestations: jerking movements due to degeneration of the caudate nucleus and star-shaped erythrocytes. Often, proteins whose mutations result in similar phenotypes function together. Both VPS13A and XK are thought to control bilayer lipids dynamics: net lipid transfer between adjacent cytosolic membrane leaflets (VPS13A) and lipid scrambling to equilibrate lipids between bilayer leaflets (XK). Accordingly, the two proteins were shown to interact, but the reported subcellular localizations of VPS13A seemed incompatible with a partnership with XK, a plasma membrane protein. Here we show that the two proteins can interact at ER-plasma membrane contacts and provide evidence that their partnership undergoes regulation by an intramolecular switch in XK.
Chorea-acanthocytosis (ChAc) and McLeod syndrome are diseases with shared clinical manifestations caused by mutations in VPS13A and XK, respectively. Key features of these conditions are the degeneration of caudate neurons and the presence of abnormally shaped erythrocytes. XK belongs to a family of plasma membrane (PM) lipid scramblases whose action results in exposure of PtdSer at the cell surface. VPS13A is an endoplasmic reticulum (ER)-anchored lipid transfer protein with a putative role in the transport of lipids at contacts of the ER with other membranes. Recently VPS13A and XK were reported to interact by still unknown mechanisms. So far, however, there is no evidence for a colocalization of the two proteins at contacts of the ER with the PM, where XK resides, as VPS13A was shown to be localized at contacts between the ER and either mitochondria or lipid droplets. Here we show that VPS13A can also localize at ER–PM contacts via the binding of its PH domain to a cytosolic loop of XK, that such interaction is regulated by an intramolecular interaction within XK, and that both VPS13A and XK are highly expressed in the caudate neurons. Binding of the PH domain of VPS13A to XK is competitive with its binding to intracellular membranes that mediate other tethering functions of VPS13A. Our findings support a model according to which VPS13A-dependent lipid transfer between the ER and the PM is coupled to lipid scrambling within the PM. They raise the possibility that defective cell surface exposure of PtdSer may be responsible for neurodegeneration.
