Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan, USA; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA.
Program in Chemical Biology, University of Michigan, Ann Arbor, Michigan, USA; Life Sciences Institute, University of Michigan, Ann Arbor, Michigan, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan, USA; Departments of Human Genetics and Pediatrics, University of Michigan, Ann Arbor, Michigan, USA.
J Lipid Res. 2022 Aug;63(8):100248. doi: 10.1016/j.jlr.2022.100248. Epub 2022 Jun 24.
The low-density lipoprotein receptor (LDLR) mediates the hepatic uptake of circulating low-density lipoproteins (LDLs), a process that modulates the development of atherosclerotic cardiovascular disease. We recently identified RAB10, encoding a small GTPase, as a positive regulator of LDL uptake in hepatocellular carcinoma cells (HuH7) in a genome-wide CRISPR screen, though the underlying molecular mechanism for this effect was unknown. We now report that RAB10 regulates hepatocyte LDL uptake by promoting the recycling of endocytosed LDLR from RAB11-positive endosomes to the plasma membrane. We also show that RAB10 similarly promotes the recycling of the transferrin receptor, which binds the transferrin protein that mediates the transport of iron in the blood, albeit from a distinct RAB4-positive compartment. Taken together, our findings suggest a model in which RAB10 regulates LDL and transferrin uptake by promoting both slow and rapid recycling routes for their respective receptor proteins.
低密度脂蛋白受体（LDLR）介导循环中的低密度脂蛋白（LDL）在肝脏中的摄取，这一过程调节动脉粥样硬化性心血管疾病的发展。我们最近在全基因组 CRISPR 筛选中鉴定出 RAB10，它编码一种小分子 GTPase，是肝细胞癌细胞（HuH7）中 LDL 摄取的正调节剂，尽管其作用的潜在分子机制尚不清楚。我们现在报告说，RAB10 通过促进从 RAB11 阳性内体到质膜的内吞 LDLR 的再循环来调节肝细胞 LDL 的摄取。我们还表明，RAB10 同样促进了转铁蛋白受体的再循环，转铁蛋白受体结合转铁蛋白，转铁蛋白在血液中运输铁，尽管它来自于不同的 RAB4 阳性隔室。总之，我们的研究结果表明，RAB10 通过促进其各自受体蛋白的慢和快速再循环途径来调节 LDL 和转铁蛋白的摄取。
