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.

体内特定货物的有效递送对分泌途径构成了重大挑战，该途径运送由约 30% 的基因组编码的产物。新合成的蛋白质和脂质货物通过 COPII 包被的囊泡开始分泌途径，由内质网 (ER) 上的 GTPase SAR1 组装，但携带脂质的脂蛋白如何与内质网中的一般蛋白质货物区分开来并选择性分泌不清楚。在这里，我们表明该过程由 GTPase SAR1B 和 SURF4（一种高效货物受体）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 的肝失活选择性地将血脂消耗到接近零并保护小鼠免受动脉粥样硬化。这些发现表明 SURF4 和 SAR1B 之间的配对协同运行了一个专门的、剂量敏感的循环脂质运输程序，同时进一步表明了治疗动脉粥样硬化和相关心脏代谢疾病的潜在转化。