Park Jae-Sook, Thorsness Mary K, Policastro Robert, McGoldrick Luke L, Hollingsworth Nancy M, Thorsness Peter E, Neiman Aaron M
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794-5215.
Department of Molecular Biology, University of Wyoming, Laramie, WY 82071.
Mol Biol Cell. 2016 Aug 1;27(15):2435-49. doi: 10.1091/mbc.E16-02-0112. Epub 2016 Jun 8.
The Vps13 protein family is highly conserved in eukaryotic cells. Mutations in human VPS13 genes result in a variety of diseases, such as chorea acanthocytosis (ChAc), but the cellular functions of Vps13 proteins are not well defined. In yeast, there is a single VPS13 orthologue, which is required for at least two different processes: protein sorting to the vacuole and sporulation. This study demonstrates that VPS13 is also important for mitochondrial integrity. In addition to preventing transfer of DNA from the mitochondrion to the nucleus, VPS13 suppresses mitophagy and functions in parallel with the endoplasmic reticulum-mitochondrion encounter structure (ERMES). In different growth conditions, Vps13 localizes to endosome-mitochondrion contacts and to the nuclear-vacuole junctions, indicating that Vps13 may function at membrane contact sites. The ability of VPS13 to compensate for the absence of ERMES correlates with its intracellular distribution. We propose that Vps13 is present at multiple membrane contact sites and that separation-of-function mutants are due to loss of Vps13 at specific junctions. Introduction of VPS13A mutations identified in ChAc patients at cognate sites in yeast VPS13 are specifically defective in compensating for the lack of ERMES, suggesting that mitochondrial dysfunction might be the basis for ChAc.
Vps13蛋白家族在真核细胞中高度保守。人类VPS13基因突变会导致多种疾病，如舞蹈病性棘红细胞增多症（ChAc），但Vps13蛋白的细胞功能尚未明确。在酵母中，有一个单一的VPS13直系同源物，它参与至少两个不同的过程：蛋白质分选至液泡和孢子形成。本研究表明，VPS13对线粒体完整性也很重要。除了防止DNA从线粒体转移到细胞核外，VPS13还抑制线粒体自噬，并与内质网 - 线粒体接触结构（ERMES）协同发挥作用。在不同的生长条件下，Vps13定位于内体 - 线粒体接触点和核 - 液泡连接处，这表明Vps13可能在膜接触位点发挥作用。VPS13补偿ERMES缺失的能力与其细胞内分布相关。我们提出Vps13存在于多个膜接触位点，功能分离突变体是由于Vps13在特定连接处缺失所致。在酵母VPS13的同源位点引入ChAc患者中鉴定出的VPS13A突变，在补偿ERMES缺失方面存在特异性缺陷，这表明线粒体功能障碍可能是ChAc的基础。
