Rab2+膜泡介导的高尔基体与自噬小体互作的分子机制

Autophagosome is a specified organelle which is synthesized during autophagy in eukaryotic cells. Many other organelles contribute to the biogenesis of autophagosomes, and conversely, autophagosome can recognize and enwrap these organelles for their lysosomal degradation, which is crucial for organelle homeostasis. Previous studies have shown that Golgi apparatus plays essential roles in autophagosome formation, however, the mechanisms remain elusive. In addition, it remains unknown whether autophagosome targets Golgi membrane structures for their lysosomal degradation. Our recent work indicates that a GM130-Rab2 signaling axis relay signals from Golgi to autophagosome, and surprisingly, autophagosome may recognize and encapsulate Golgi-derived vesicles to facilitate their degradation. Therefore, we hypothesize that Golgi apparatus donates Rab2+ vesicles to form autophagosome, and that autophagosome targets Golgi-derived Rab2+ vesicles for degradation to maintain the homeostasis of Golgi structure. In this study, we aim to further investigate the molecular mechanism underlying the Golgi-autophagosome interplay, and the upstream signaling pathway. Our work will elucidate a novel mechanism mediating the signal exchange between Golgi and autophagosome, and help to deepen our understanding in inter-organelle interaction network.

自噬小体是真核细胞自噬过程中形成的一种特有的细胞器，其生成需要其他多种细胞器提供膜组分；而自噬小体则能够识别并包裹多种细胞器，将其运送至溶酶体降解，从而调控其稳态。研究表明，高尔基体在自噬小体生成过程中发挥重要作用，但机制不明；自噬小体能否吞噬高尔基体膜泡及其分子机制尚未知。我们近期研究发现外界胁迫信号经由GM130-Rab2信号轴，从高尔基体向自噬小体传导；自噬小体识别并包裹Rab2标记（Rab2+）的高尔基体膜泡，促进其降解。基于此，我们提出科学假设：高尔基体通过Rab2+膜泡向正在形成的自噬小体输送膜原料；而自噬小体可以吞噬Rab2+膜泡以维持高尔基体的稳态。本项目拟在上述工作的基础上，深入研究Rab2+膜泡介导的高尔基体与自噬小体互作的分子机制，揭示其上游调控信号通路。本研究将阐明高尔基体与自噬小体之间通过相互调控而响应外界刺激的分子机制，相关发现将加深我们对细胞器互作网络的认识。

细胞自噬是一种溶酶体降解途径，对细胞内稳态维持至关重要。自噬异常与多种人类疾病密切相关。研究表明，自噬小体的从头合成需要多种来源的膜结构参与，包括内质网、高尔基体和线粒体等。但不同来源的膜组分如何定向输送促进完整的自噬小体形成的分子机制尚不清楚。ATG9是至今鉴定的唯一自噬相关跨膜蛋白，在细胞内广泛分布，已有研究表明ATG9阳性（ATG9+）膜结构是自噬膜的重要来源。但目前尚不清楚高尔基体来源的ATG9+小泡是如何转运并整合到哺乳动物细胞的早期自噬结构中。我们在本项目的支持下研究发现，高尔基体通过贡献Rab2+ Atg9+囊泡来促进自噬启动，在自噬诱导条件下，原先锚定于GM130的Rab2+ Atg9+囊泡离开高尔基体，通过招募和激活ULK1参与隔离膜的形成，以此促进自噬起始。随后，Rab2转而与Pacer和Stx17相互作用成为自噬小体GTP酶，精确调控HOPS复合物向自噬小体的募集，以备与溶酶体融合。该研究不仅发现Rab2作为一种独特的GTPase参与哺乳动物细胞自噬小体和自噬溶酶体的形成，并且为高尔基体如何参与细胞自噬提供了进一步的机制性见解。