德国弗莱堡大学Claudine Kraft等研究人员合作发现，货物上启动中心的相分离是选择性自噬的触发开关。2025年1月7日，国际知名学术期刊《自然—细胞生物学》在线发表了这一成果。

研究人员发现关键的自噬生物生成因子在酵母中相分离成货物表面的启动中心，随后成熟为驱动自噬小体核化的位点。这种相分离依赖于自噬受体与货物之间的多价、低亲和力相互作用，形成一个动态的货物表面。值得注意的是，自噬受体与货物复合物之间的高亲和力相互作用会阻止启动中心的形成和自噬进程。

基于这些原理，研究人员将哺乳动物重病毒非结构蛋白µNS转化为新型货物，后者作为粒子在酵母细胞质中积累并未被降解，最终通过选择性自噬被降解。研究人员还展示了启动中心也在不同货物的表面形成，并且在建立与内质网的连接中起着关键作用，内质网是自噬小体组装位点的形成场所，从而启动自噬小体的生物合成。

总的来说，该研究表明，受调控的相分离在演化上多样的生物中都在大宗自噬和选择性自噬的启动中发挥着重要作用。

据介绍，自噬是一个关键的细胞质量控制机制。营养应激会触发大宗自噬，在形成和液-液相分离的自噬相关基因1（Atg1）复合物中，非选择性地降解细胞质物质。与此相反，选择性自噬通过自噬受体靶向去除蛋白聚集体、受损的细胞器及其他货物。货物的相分离已被观察到，但其调控机制和对选择性自噬的影响尚不清楚。

附：英文原文

Title: Phase separation of initiation hubs on cargo is a trigger switch for selective autophagy

Author: Licheva, Mariya, Pflaum, Jeremy, Babic, Riccardo, Mancilla, Hector, Elssser, Jana, Boyle, Emily, Hollenstein, David M., Jimenez-Niebla, Jorge, Pleyer, Jonas, Heinrich, Mio, Wieland, Franz-Georg, Brenneisen, Joachim, Eickhorst, Christopher, Brenner, Johann, Jiang, Shan, Hartl, Markus, Welsch, Sonja, Hunte, Carola, Timmer, Jens, Wilfling, Florian, Kraft, Claudine

Issue&Volume: 2025-01-07

Abstract: Autophagy is a key cellular quality control mechanism. Nutrient stress triggers bulk autophagy, which nonselectively degrades cytoplasmic material upon formation and liquid–liquid phase separation of the autophagy-related gene 1 (Atg1) complex. In contrast, selective autophagy eliminates protein aggregates, damaged organelles and other cargoes that are targeted by an autophagy receptor. Phase separation of cargo has been observed, but its regulation and impact on selective autophagy are poorly understood. Here, we find that key autophagy biogenesis factors phase separate into initiation hubs at cargo surfaces in yeast, subsequently maturing into sites that drive phagophore nucleation. This phase separation is dependent on multivalent, low-affinity interactions between autophagy receptors and cargo, creating a dynamic cargo surface. Notably, high-affinity interactions between autophagy receptors and cargo complexes block initiation hub formation and autophagy progression. Using these principles, we converted the mammalian reovirus nonstructural protein μNS, which accumulates as particles in the yeast cytoplasm that are not degraded, into a neo-cargo that is degraded by selective autophagy. We show that initiation hubs also form on the surface of different cargoes in human cells and are key to establish the connection to the endoplasmic reticulum, where the phagophore assembly site is formed to initiate phagophore biogenesis. Overall, our findings suggest that regulated phase separation underscores the initiation of both bulk and selective autophagy in evolutionarily diverse organisms.

DOI: 10.1038/s41556-024-01572-y

Source: https://www.nature.com/articles/s41556-024-01572-y