Mechanism of Lamellar Body Formation by Lung Surfactant Protein B. Sever et al.

Breathing depends on pulmonary surfactant, a mixture of phospholipids and proteins, secreted by alveolar type II cells. Surfactant requires lamellar bodies (LB), 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 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（pulmonary surfactant）——一种由II型肺泡细胞（alveolar type II cells）分泌的磷脂与蛋白质混合物。表面活性物质的储存与分泌依赖于板层小体（lamellar bodies, LB），这类细胞器内含致密堆叠的同心膜层结构。板层小体的生物发生机制仍不明朗，但该过程需要表面活性蛋白B（surfactant protein B, SP-B）参与：SP-B最初以前体pre-proSP-B的形式合成，随后在转运过程中被裂解为三种相关蛋白。本研究阐明了这些蛋白在板层小体形成过程中的功能与协同作用。我们证实，proSP-B的N端结构域是一种磷脂结合与转运蛋白，其活性对于proSP-B从内质网（Endoplasmic Reticulum, ER）的输出、向板层小体的分选、proSP-B向脂蛋白颗粒的转化，以及小鼠的新生存活率均不可或缺。C端结构域则促进proSP-B从内质网的输出。经proSP-B蛋白水解裂解后产生的成熟中间结构域，可形成板层小体标志性的独特膜层结构。综上，本研究结果为板层小体的生物发生过程构建了一套机制模型。