Breathing depends on pulmonary surfactant, a mixture of phospholipids and proteins, secreted by alveolar type II cells. Surfactant requires lamellar bodies (LBs), organelles containing densely packed concentric membrane layers, for storage and secretion. LB biogenesis remains mysterious but requires surfactant protein B (SP-B), which is synthesized as a precursor (pre-proSP-B) that is cleaved during trafficking into three related proteins. Here, we elucidate the functions and cooperation of these proteins in LB formation. We show that the N-terminal domain of proSP-B is a phospholipid-binding and -transfer protein whose activities are required for proSP-B export from the endoplasmic reticulum (ER) and sorting to LBs, the conversion of proSP-B into lipoprotein particles, and neonatal viability in mice. The C-terminal domain facilitates ER export of proSP-B. The mature middle domain, generated after proteolytic cleavage of proSP-B, generates the striking membrane layers characteristic of LBs. Together, our results lead to a mechanistic model of LB biogenesis.

呼吸依赖于肺表面活性物质，一种磷脂和蛋白质的混合物，由肺泡 II 型细胞分泌。表面活性剂需要层状体 (LBs)，即含有密集排列的同心膜层的细胞器，用于储存和分泌。LB 的生物发生仍然很神秘，但需要表面活性蛋白 B (SP-B)，它是作为前体 (pre-proSP-B) 合成的，在运输过程中被切割成三种相关的蛋白质。在这里，我们阐明了这些蛋白质在 LB 形成中的功能和合作。我们表明 proSP-B 的 N 端结构域是一种磷脂结合和转移蛋白，其活性是 proSP-B 从内质网 (ER) 输出和分选到 LBs、proSP-B 转化为脂蛋白所必需的。颗粒和小鼠的新生儿活力。C 末端结构域促进 proSP-B 的 ER 输出。proSP-B 蛋白水解切割后产生的成熟中间结构域产生 LBs 的引人注目的膜层特征。总之，我们的结果导致了 LB 生物发生的机械模型。