Institut de Recherches Cliniques de Montréal (IRCM), Montréal, QC, H2W 1R7, Canada.
Département de Médecine (Programmes de Biologie Moléculaire), Université de Montréal, Montréal, QC, H3T 1J4, Canada.
Nat Commun. 2018 Oct 26;9(1):4470. doi: 10.1038/s41467-018-06897-5.
Myoblast fusion is tightly regulated during development and regeneration of muscle fibers. BAI3 is a receptor that orchestrates myoblast fusion via Elmo/Dock1 signaling, but the mechanisms regulating its activity remain elusive. Here we report that mice lacking BAI3 display small muscle fibers and inefficient muscle regeneration after cardiotoxin-induced injury. We describe two proteins that repress or activate BAI3 in muscle progenitors. We find that the secreted C1q-like1-4 proteins repress fusion by specifically interacting with BAI3. Using a proteomic approach, we identify Stabilin-2 as a protein that interacts with BAI3 and stimulates its fusion promoting activity. We demonstrate that Stabilin-2 activates the GPCR activity of BAI3. The resulting activated heterotrimeric G-proteins contribute to the initial recruitment of Elmo proteins to the membrane, which are then stabilized on BAI3 through a direct interaction. Collectively, our results demonstrate that the activity of BAI3 is spatiotemporally regulated by C1qL4 and Stabilin-2 during myoblast fusion.
成肌细胞融合在肌肉纤维的发育和再生过程中受到严格调控。BAI3 是一种通过 Elmo/Dock1 信号协调成肌细胞融合的受体，但调节其活性的机制仍不清楚。在这里，我们报告说，缺乏 BAI3 的小鼠在心脏毒素诱导损伤后表现出小肌肉纤维和低效的肌肉再生。我们描述了两种在肌肉祖细胞中抑制或激活 BAI3 的蛋白质。我们发现，分泌的 C1q 样蛋白 1-4 通过特异性与 BAI3 相互作用来抑制融合。使用蛋白质组学方法，我们鉴定出 Stabilin-2 是一种与 BAI3 相互作用并刺激其融合促进活性的蛋白质。我们证明了 Stabilin-2 激活了 BAI3 的 GPCR 活性。由此产生的激活的三聚体 G 蛋白有助于最初将 Elmo 蛋白募集到膜上，然后通过直接相互作用将其稳定在 BAI3 上。总的来说，我们的结果表明，在成肌细胞融合过程中，BAI3 的活性受到 C1qL4 和 Stabilin-2 的时空调节。
