Pacer Mediates the Function of Class III PI3K and HOPS Complexes in Autophagosome Maturation by Engaging Stx17
Pacer Mediates the Function of Class III PI3K and HOPS Complexes in Autophagosome Maturation by Engaging Stx17
复制标题
Pacer 通过接合 Stx17 介导 III 类 PI3K 和 HOPS 复合物在自噬体成熟中的功能
DOI：
10.1016/j.molcel.2017.02.010
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发表时间：
2017-03-16
期刊：
影响因子：
16
通讯作者：
Sun, Qiming
中科院分区：
文献类型：
--
作者：
Cheng, Xiawei;Ma, Xiuling;Sun, Qiming
III 类 PI3 激酶 (PI3KC3) 对于自噬启动至关重要，但 PI3KC3 是否参与自噬的其他步骤仍不清楚。 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连接到溶酶体仍不清楚。在这里，我们报告 Pacer（与作为自噬增强剂的 UVRAG 相关的蛋白质）作为自噬的调节剂。 Pacer 定位于自噬结构并积极调节自噬体成熟。从机制上讲，Pacer 拮抗 Rubicon 以刺激 Vps34 激酶活性。接下来，Pacer 将 PI3KC3 和 HOPS 复合物招募到自噬体中，通过锚定到自噬体 SNARE Stx17 来进行位点特异性激活。此外，Pacer 对于肝脏脂滴的降解、沙门氏菌感染的抑制以及蛋白质聚集物的清除至关重要。这些结果不仅表明 Pacer 是自噬中重要的多功能增强子，而且还揭示了 PI3KC3 的参与以及 HOPS 在自噬体成熟过程中的特异性束缚活性的介体。
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 autophagosometo 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 auto-phagosomal 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.