饮食中胆固醇的过多摄取是心脑血管疾病的诱因之一。Niemann-Pick Type C1-Like 1 (NPC1L1)蛋白是介导小肠吸收饮食胆固醇的关键蛋白质。在细胞胆固醇水平较低时NPC1L1蛋白会转运到质膜上，向细胞供给胆固醇将促使NPC1L1蛋白和胆固醇一起吞进细胞里。先前的工作揭示了NPC1L1蛋白转运依赖于微丝以及MyoVb•Rab11a•Rab11-FIP2三元复合物，但是胆固醇如何调控这一过程还不清楚。
发现小肠中吸收胆固醇的关键蛋白
8月15日，《生物化学期刊》（The Journal of Biological Chemistry）在线发表了中科院上海生命科学研究院生化与细胞所宋保亮研究组关于小GTP酶Cdc42调控NPC1L1蛋白向质膜转运的最新研究结果。该研究发现，低胆固醇信号刺激Cdc42的激活，而活性的Cdc42能够结合NPC1L1蛋白。同时，活性的Cdc42通过下游效应物N-WASP和Arp2/3复合物的依次活化介导分支状微丝的动态组装，促进NPC1L1蛋白与Rab11a的解离，并促使MyoVb将NPC1L1运输到质膜。Cdc42肝脏特异性敲除小鼠模型进一步证明了NPC1L1的组织定位与胆固醇吸收功能都依赖于Cdc42。
这项工作主要由博士研究生谢畅完成，该课题获得国家科技部、国家自然科学基金委、中国科学院和上海市科委的经费资助。
生物探索推荐英文摘要
The small GTPase Cdc42 interacts with Niemann-Pick C1 Like 1 (NPC1L1) and controls its movement from endocytic recycling compartment to plasma membrane in a cholesterol dependent manner
Niemann-Pick C1 Like 1 (NPC1L1) is a multi-transmembrane protein that mediates the absorption of dietary and biliary cholesterol through vesicular endocytosis. The subcellular localization of NPC1L1 is regulated by cholesterol. Cholesterol depletion induces the transport of NPC1L1 to plasma membrane (PM) from endocytic recycling compartment that requires MyoVb-Rab11a-Rab11FIP2 triple complex, and cholesterol-replenishment renders the internalization of NPC1L1 together with cholesterol. Here, we find that GTP-bound Cdc42 interacts with NPC1L1. Cholesterol depletion regulates the activation of Cdc42 and enhances NPC1L1-Cdc42 interaction. Over-expression of constitutive GTP-bound Cdc42 mutant form or knockdown of Cdc42 inhibits the transport of NPC1L1 to the PM and disturbs the cholesterol-regulated binding of NPC1L1 to Rab11a, MyoVb and actin. Knockdown of Cdc42 downstream effectors N-WASP or Arp3 also leads to the similar results. In liver specific Cdc42 knockout (Cdc42 LKO) mice, NPC1L1 fails to localize to bile canaliculi, and the biliary cholesterol cannot be efficiently reabsorbed. These results indicate that Cdc42 controls the cholesterol-regulated transport and localization of NPC1L1, and plays a role in cholesterol absorption.
