State Key Laboratory of Membrane Biology, Peking University, Beijing 100871, China; Institute of Molecular Medicine, Peking University, Beijing 100871, China.
Center for Life Sciences, Peking University, Beijing 100871, China.
Cell Metab. 2021 Feb 2;33(2):350-366.e7. doi: 10.1016/j.cmet.2020.10.020. Epub 2020 Nov 12.
Efficient delivery of specific cargos in vivo poses a major challenge to the secretory pathway, which shuttles products encoded by ∼30% of the genome. Newly synthesized protein and lipid cargos embark on the secretory pathway via COPII-coated vesicles, assembled by the GTPase SAR1 on the endoplasmic reticulum (ER), but how lipid-carrying lipoproteins are distinguished from the general protein cargos in the ER and selectively secreted has not been clear. Here, we show that this process is quantitatively governed by the GTPase SAR1B and SURF4, a high-efficiency cargo receptor. While both genes are implicated in lipid regulation in humans, hepatic inactivation of either mouse Sar1b or Surf4 selectively depletes plasma lipids to near-zero and protects the mice from atherosclerosis. These findings show that the pairing between SURF4 and SAR1B synergistically operates a specialized, dosage-sensitive transport program for circulating lipids, while further suggesting a potential translation to treat atherosclerosis and related cardio-metabolic diseases.
在体内有效输送特定货物对分泌途径构成了重大挑战，该途径转运约 30%基因组编码的产物。新合成的蛋白质和脂类货物通过内质网（ER）上的 GTPase SAR1 组装的 COPII 包被小泡进入分泌途径，但 ER 中如何区分载脂蛋白和一般蛋白质货物并进行选择性分泌尚不清楚。在这里，我们表明这个过程受到 GTPase SAR1B 和 SURF4（一种高效货物受体）的定量控制。虽然这两个基因都与人类的脂质调节有关，但小鼠 Sar1b 或 Surf4 的肝性失活选择性地将血浆脂质消耗至接近零，并保护小鼠免受动脉粥样硬化的侵害。这些发现表明，SURF4 和 SAR1B 之间的配对协同作用为循环脂质提供了一种专门的、剂量敏感的运输程序，同时进一步表明了一种治疗动脉粥样硬化和相关心血管代谢疾病的潜在转化方法。
