Xu Peng, Mancuso Rubia Isler, Leonzino Marianna, Zeiss Caroline J, Krause Diane S, De Camilli Pietro
Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Department of Cell biology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
bioRxiv. 2025 May 13:2025.05.09.653147. doi: 10.1101/2025.05.09.653147.
VPS13 is the founding member of a family of proteins that mediate lipid transfer at intracellular membrane contact sites by a bridge-like mechanism. Mammalian genomes comprise 4 genes encoding proteins with distinct localizations and function. The gene duplication resulting in and is the most recent in evolution and, accordingly, these two proteins are the most similar to each other. However, they have distinct subcellular localizations and their loss of function mutations in humans are compatible with life but result in two different age-dependent neurodegenerative diseases, chorea-acanthocytosis and Parkinson's disease, respectively. Thus, it remains unclear whether these two proteins have overlapping functions. Here, we show that while KO and KO mice are viable, embryonic development of double knockout (DKO) mice is arrested at midgestation. Prior to death, DKO embryos were smaller than controls, were anemic and had a smaller liver, the key erythropoietic site at this developmental stage. Further analyses of erythroid precursor cells showed that their differentiation was impaired and that this defect was accompanied by activation of innate immunity as revealed by upregulation of interferon stimulated genes (ISGs). Additionally, the RIG-I and MDA5 components of dsRNA triggered innate immunity were found upregulated in the DKO fetal liver. Activation of innate immunity may result from loss of integrity of the membranes of intracellular organelles, such as mitochondria and autophagic lysosomes, due to the absence of these lipid transport proteins. The surprising and striking synthetic effect resulting for the combined loss of VPS13A and VPS13C suggests that despite of the different localization of these two proteins, the lipid fluxes that they mediate are partially redundant.
VPS13是一类蛋白质家族的创始成员，该家族通过类似桥梁的机制在细胞内膜接触位点介导脂质转运。哺乳动物基因组包含4个基因，这些基因编码具有不同定位和功能的蛋白质。导致VPS13A和VPS13C的基因复制是进化过程中最新发生的，因此，这两种蛋白质彼此最为相似。然而，它们具有不同的亚细胞定位，并且它们在人类中的功能丧失突变与生命相容，但分别导致两种不同的年龄依赖性神经退行性疾病，即舞蹈病-棘红细胞增多症和帕金森病。因此，这两种蛋白质是否具有重叠功能仍不清楚。在这里，我们表明，虽然VPS13A基因敲除（KO）和VPS13C基因敲除小鼠是存活的，但VPS13A和VPS13C双敲除（DKO）小鼠的胚胎发育在妊娠中期停滞。在死亡之前，DKO胚胎比对照组小，患有贫血，并且肝脏较小，肝脏是这个发育阶段关键的红细胞生成部位。对红系前体细胞的进一步分析表明，它们的分化受损，并且这种缺陷伴随着先天免疫的激活，这通过干扰素刺激基因（ISG）的上调得以揭示。此外，在DKO胎儿肝脏中发现双链RNA触发的先天免疫的RIG-I和MDA5成分上调。先天免疫的激活可能是由于缺乏这些脂质转运蛋白导致细胞内细胞器（如线粒体和自噬溶酶体）膜的完整性丧失。VPS13A和VPS13C联合缺失产生的惊人且显著的合成效应表明，尽管这两种蛋白质定位不同，但它们介导的脂质通量部分是冗余的。
