Wetting regulates autophagy of phase-separated compartments and the cytosol
Wetting regulates autophagy of phase-separated compartments and the cytosol
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DOI：
10.1038/s41586-020-2992-3
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发表时间：
2020-12-09
期刊：
影响因子：
64.8
通讯作者：
Knorr, Roland L.
中科院分区：
文献类型：
--
作者：
Agudo-Canalejo, Jaime;Schultz, Sebastian W.;Knorr, Roland L.
液滴状结构中细胞材料的区室化是液-液相分离的标志（1，2），但液滴去除的机制知之甚少。有证据表明，液滴可以通过自噬降解（3，4），自噬是一种高度保守的降解系统，其中膜片弯曲以分离双膜自噬体内的部分细胞质（5-7）。在这里，我们研究了自噬体如何在活细胞中隔离含有蛋白质p62（也称为SQSTM 1）的液滴，并证明了双膜自噬体样囊泡通过部分润湿在体外无蛋白液滴的表面形成。一个最小的物理模型表明，液滴表面张力支持膜片的形成。该模型还预测，弯曲板要么分割液滴的零碎隔离或隔离整个液滴。我们发现，自噬体螯合是强大的液滴片粘附强度的变化。但部分润湿的片层的两侧暴露于不同的环境中，这可以决定自噬体片层的弯曲方向。我们发现液滴和膜片的材料特性之间的这种相互作用使我们能够阐明液滴自噬或“流体吞噬”的机制。此外，我们发现了一种转换机制，允许液滴作为细胞溶质降解自噬体的液体组装平台（8）或作为特异性自噬底物（9-11）。我们提出，液滴介导的自噬代表了以前未描述的一类由弹性毛细血管驱动的过程，突出了润湿在细胞溶质组织中的重要性。
Compartmentalization of cellular material in droplet-like structures is a hallmark of liquid-liquid phase separation(1,2), but the mechanisms of droplet removal are poorly understood. Evidence suggests that droplets can be degraded by autophagy(3,4), a highly conserved degradation system in which membrane sheets bend to isolate portions of the cytoplasm within double-membrane autophagosomes(5-7). Here we examine how autophagosomes sequester droplets that contain the protein p62 (also known as SQSTM1) in living cells, and demonstrate that double-membrane, autophagosome-like vesicles form at the surface of protein-free droplets in vitro through partial wetting. A minimal physical model shows that droplet surface tension supports the formation of membrane sheets. The model also predicts that bending sheets either divide droplets for piecemeal sequestration or sequester entire droplets. We find that autophagosomal sequestration is robust to variations in the droplet-sheet adhesion strength. However, the two sides of partially wetted sheets are exposed to different environments, which can determine the bending direction of autophagosomal sheets. Our discovery of this interplay between the material properties of droplets and membrane sheets enables us to elucidate the mechanisms that underpin droplet autophagy, or 'fluidophagy'. Furthermore, we uncover a switching mechanism that allows droplets to act as liquid assembly platforms for cytosol-degrading autophagosomes(8) or as specific autophagy substrates(9-11). We propose that droplet-mediated autophagy represents a previously undescribed class of processes that are driven by elastocapillarity, highlighting the importance of wetting in cytosolic organization.