Pacer调控自噬溶酶体形成的分子机制研究

III型PI3K激酶(PI3KC3)复合物在自噬小体形成起始阶段发挥关键作用，但尚不了解该复合物是否调控自噬溶酶体形成。HOPS复合物调控膜泡与溶酶体的融合，但尚不明确HOPS促进自噬溶酶体形成的机制。Rubicon是PI3KC3的抑制性亚基，近期我们发现一个和Rubicon有31%的序列相似度的蛋白KIAA0226L（在本研究中命名为Pacer）是一个新的自噬增强因子。初步的研究表明Pacer定位于自噬小体,它一方面通过拮抗Rubicon而激活PI3KC3；另一方面通过招募HOPS复合物到自噬小体，而促进自噬溶酶体形成。本项目将进一步深入研究Pacer的作用分子机制，相关研究成果将回答前述科学问题，对揭示自噬溶酶体形成分子机制具有重要意义。

Class III PI3K (PI3KC3) is essential for autophagosome initiation, whether PI3KC3 participates in autolysosome formation remains unknown. The mammalian homotypic fusion and vacuole protein sorting (HOPS) is the tethering complex required for fusion of intracellular vesicles to lysosome, how HOPS specifically tethers autophagosome to lysosome remains elusive. Rubicon is the inhibitory subunit of PI3KC3. Recently, we found that KIAA0226L (named as Pacer in this study), a protein which shares 31% sequence similarity with Rubicon, is a novel autophagy enhancer. Mechanistically, Pacer localizes to autophagosome and stimulatesVps34 kinase activity by antagonizing Rubicon, meanwhile, Pacer may also recruit HOPS complex to autophagosome to facilitate autolysosome formation. In this study, we aim to further dissect Pacer’s function in late stage of autophagy. Our findings will answer the above-mentioned scientific questions, and will advance our understanding in the regulatory mechanism of autolysosome formation.