Lee Daniel S W, Oster Liya F, Son Sungmin, Fletcher Daniel A
Department of Bioengineering, University of California, Berkeley, CA 94720.
Graduate Group in Biophysics, Berkeley, CA 94720.
bioRxiv. 2024 Dec 13:2024.12.12.628283. doi: 10.1101/2024.12.12.628283.
Cell-cell fusion is fundamental to developmental processes such as muscle formation, as well as to viral infections that cause pathological syncytia. An essential step in fusion is close membrane apposition, but cell membranes are crowded with proteins, glycoproteins, and glycolipids, all of which must be cleared before a fusion pore can be nucleated. Here, we find that cell surface crowding drastically reduces fusogenicity in multiple systems, independent of the method for driving fusion. We estimate that cell surface crowding presents an energetic barrier to membrane apposition on the scale of , greater than that of bare membrane fusion. We show that increasing cell surface crowding reduces fusion efficiency of PEG-mediated and fusogen-mediated cell-cell fusion, as well as synthetic membranes under force. Interestingly, we find that differentiating myoblasts naturally decrease cell surface crowding prior to fusion. Cell surface crowding presents an underappreciated biophysical barrier that may be tuned developmentally and could be targeted externally to control tissue-specific cell-cell fusion.
细胞间融合对于诸如肌肉形成等发育过程以及导致病理性多核体的病毒感染至关重要。融合的一个关键步骤是细胞膜紧密并列，但细胞膜上挤满了蛋白质、糖蛋白和糖脂，在形成融合孔之前所有这些都必须清除。在这里，我们发现细胞表面的拥挤显著降低了多个系统中的融合能力，这与驱动融合的方法无关。我们估计细胞表面拥挤对膜并列形成了一个能量屏障，其规模为 ，大于裸露膜融合的能量屏障。我们表明，增加细胞表面拥挤会降低聚乙二醇介导的和融合素介导的细胞间融合以及受力下合成膜的融合效率。有趣的是，我们发现分化中的成肌细胞在融合前会自然减少细胞表面拥挤。细胞表面拥挤是一个未得到充分认识的生物物理屏障，它可能在发育过程中得到调节，并且可以从外部进行靶向调控以控制组织特异性细胞间融合。
