内质网与自噬溶酶体互作的分子机制

The organelle interaction is extremely important for normal physiological functions in cells. Especially under various environmental stimuli, the cells will adapt to changes in the environment by changing the interaction network between organelles. Upon some stimulating conditions such as starvation, autophagosomes carrying the membrane components of endoplasmic reticulum, mitochondria, plasma membranes, Golgi and other organelles fuse with lysosomes to form autolysosomes. The lysosomal components of autolysosomes are recycled by autophagic lysosome reformation (ALR), but the fate of the endoplasmic reticulum membrane components is not yet known. Our preliminary data showed that the endoplasmic reticulum components on autolysosomes are not degraded but recycled in a completely novel pathway. We named this pathway as ERCRA. This is the first time to observe the recycling process of endoplasmic reticulum components on autolysosomes. Therefore, the applicant seeks to use cell biology, genetics, biochemistry, biophysics and other means to thoroughly study the molecular mechanism and physiological functions of ERCRA and the position and relationship of ERCRA in the organelle interaction network. The proposed study would provide detailed interpretation of the interaction and material exchange between endoplasmic reticulum and lysosomes, but also provide further understanding of the interactions diversity and complexity between organelles when cells are exposed to various external stimuli.

细胞器相互作用对于细胞执行正常的生理功能是极其重要的，尤其在各种外界环境刺激下，细胞会通过改变细胞器间的互作网络来适应外界的环境变化。在饥饿等刺激条件下，自噬体携带着内质网、线粒体、细胞膜和高尔基体等膜成分与溶酶体融合形成自噬溶酶体。在自噬溶酶体上溶酶体成分通过自噬性溶酶体再生（ALR）进行回收利用，但是内质网膜成分的命运如何还不清楚。我们的前期研究结果发现自噬溶酶体上的内质网成分不会被降解而是以一种全新的方式被循环利用，我们称这种现象为ERCRA。这是首次发现内质网成分在自噬溶酶体上的循环利用。因此申请人拟采用细胞生物学、遗传学、生物化学、生物物理学等手段深入研究ERCRA的分子机制和生理功能以及ERCRA在细胞器互作网络里的位置和关系。本课题的顺利进展不仅有利于阐释内质网与溶酶体之间的互作机制，也有助于我们进一步认识在细胞面临各种外界刺激时，细胞器间相互作用的多样性、复杂性和协作性。

自噬溶酶体的膜成分来源于自噬体和溶酶体。自噬体内容物在自噬溶酶体腔内降解，但是自噬体外膜成分的命运未知。我们发现自噬体的外膜成分并没有被降解，而是被分选循环利用。我们将这个过程命名为自噬体成分循环（ACR）。我们进一步的研究鉴定了一个由SNX4、 SNX5、SNX17组成的三元蛋白质复合体。我们将其命名为recycler。Recyler负责了自噬体成分循环这个过程。其中SNX4和SNX5形成一个异源二聚体，通过它们的BAR结构域来识别自噬体膜成分并使膜变形。SNX17与Dynein-dynactin复合体及SNX4-SNX5异源二聚体执行自噬体循环。自噬体成分循环的发现和recycler的鉴定揭示了一个自噬溶酶体上的重要分选循环途径。