Myomaker and Myomerger Work Independently to Control Distinct Steps of Membrane Remodeling during Myoblast Fusion.

Classic mechanisms for membrane fusion involve transmembrane proteins that assemble into complexes and dynamically alter their conformation to bend membranes, leading to mixing of membrane lipids (hemifusion) and fusion pore formation. Myomaker and Myomerger govern myoblast fusion and muscle formation, but are structurally divergent from traditional fusogenic proteins. Here, we show that Myomaker and Myomerger independently mediate distinct steps in the fusion pathway, where Myomaker is involved in membrane hemifusion and Myomerger is necessary for fusion pore formation. Mechanistically, we demonstrate that Myomerger is required on the cell surface where its ectodomains stress membranes. Moreover, we show that Myomerger drives fusion completion in a heterologous system independent of Myomaker, and that a Myomaker-Myomerger physical interaction is not required for function. Collectively, our data identify a step-wise cell fusion mechanism in myoblasts where different proteins are delegated to perform unique membrane functions essential for membrane coalescence. An eTOC blurb should also be included that is no longer than 50 words describing the context and significance of the findings for the broader journal readership. When writing this paragraph, please target it to non-specialists by highlighting the major conceptual point of the paper in plain language, without extensive experimental detail. The blurb must be written in the third person and refer to “First Author et al.” Myoblast fusion is essential for muscle development, regeneration, and growth. Leikina et al. reveal that myoblasts proceed through a fusion mechanism characterized by a division of labor between muscle fusion proteins. The independent and sequential membrane functions of different proteins (Myomaker and Myomerger) culminate in membrane coalescence.

经典的膜融合机制涉及跨膜蛋白，这些蛋白组装成复合物并动态改变其构象以弯曲膜，从而导致膜脂混合（半融合）和融合孔形成。Myomaker和Myomerger调控成肌细胞融合与肌肉形成，但在结构上与传统的促融合蛋白不同。在此，我们表明Myomaker和Myomerger在融合途径中各自介导不同步骤，Myomaker参与膜半融合，而Myomerger是融合孔形成所必需的。从机制上讲，我们证明Myomerger在细胞表面发挥作用，其胞外域对膜施加应力。此外，我们发现Myomerger可在不依赖Myomaker的异源系统中驱动融合完成，且Myomaker与Myomerger之间的物理相互作用并非其功能所必需。总体而言，我们的数据确定了成肌细胞中的一种分步式细胞融合机制，即不同蛋白质各司其职，执行膜融合所必需的独特膜功能。 **论文亮点**：成肌细胞融合对肌肉发育、再生和生长至关重要。Leikina等人揭示，成肌细胞通过一种融合机制进行融合，其特点是肌肉融合蛋白间存在分工。不同蛋白（Myomaker和Myomerger）独立且有序的膜功能最终促成膜融合。