Department of Biochemistry and Molecular Biology, School of Medicine, Zhejiang University, Hangzhou 310058, China.
National Institute of Biological Sciences, Beijing 102206, China.
Mol Cell. 2017 Mar 16;65(6):1029-1043.e5. doi: 10.1016/j.molcel.2017.02.010.
Class III PI3-kinase (PI3KC3) is essential for autophagy initiation, but whether PI3KC3 participates in other steps of autophagy remains unknown. The HOPS complex mediates the fusion of intracellular vesicles to lysosome, but how HOPS specifically tethers autophagosome to lysosome remains elusive. Here, we report Pacer (protein associated with UVRAG as autophagy enhancer) as a regulator of autophagy. Pacer localizes to autophagic structures and positively regulates autophagosome maturation. Mechanistically, Pacer antagonizes Rubicon to stimulate Vps34 kinase activity. Next, Pacer recruits PI3KC3 and HOPS complexes to the autophagosome for their site-specific activation by anchoring to the autophagosomal SNARE Stx17. Furthermore, Pacer is crucial for the degradation of hepatic lipid droplets, the suppression of Salmonella infection, and the clearance of protein aggregates. These results not only identify Pacer as a crucial multifunctional enhancer in autophagy but also uncover both the involvement of PI3KC3 and the mediators of HOPS's specific tethering activity in autophagosome maturation.
III 类 PI3-激酶 (PI3KC3) 对自噬的起始至关重要，但 PI3KC3 是否参与自噬的其他步骤尚不清楚。HOPS 复合物介导细胞内囊泡与溶酶体的融合，但 HOPS 如何特异性地将自噬体与溶酶体连接仍然难以捉摸。在这里，我们报告 Pacer（与 UVRAG 相关的蛋白作为自噬增强子）作为自噬的调节剂。Pacer 定位于自噬结构中，并正向调节自噬体成熟。在机制上，Pacer 拮抗 Rubicon 来刺激 Vps34 激酶活性。接下来，Pacer 将 PI3KC3 和 HOPS 复合物招募到自噬体上，通过锚定自噬体 SNARE Stx17 来特异性激活它们。此外，Pacer 对于肝脂滴的降解、沙门氏菌感染的抑制和蛋白聚集体的清除至关重要。这些结果不仅鉴定了 Pacer 作为自噬中关键的多功能增强子，还揭示了 PI3KC3 的参与以及 HOPS 特异性连接活性的介质在自噬体成熟中的作用。
