Sun Aiqin, Wei Jing, Childress Chandra, Shaw John H, Peng Ke, Shao Genbao, Yang Wannian, Lin Qiong
a School of Medicine, Jiangsu University , Zhenjiang , China.
b Department of Biology , Susquehanna University , Selinsgrove , PA , USA.
Autophagy. 2017 Mar 4;13(3):522-537. doi: 10.1080/15548627.2016.1268301. Epub 2017 Jan 13.
The MAP1LC3/LC3 family plays an essential role in autophagosomal biogenesis and transport. In this report, we show that the HECT family E3 ubiquitin ligase NEDD4 interacts with LC3 and is involved in autophagosomal biogenesis. NEDD4 binds to LC3 through a conserved WXXL LC3-binding motif in a region between the C2 and the WW2 domains. Knockdown of NEDD4 impaired starvation- or rapamycin-induced activation of autophagy and autophagosomal biogenesis and caused aggregates of the LC3 puncta colocalized with endoplasmic reticulum membrane markers. Electron microscopy observed gigantic deformed mitochondria in NEDD4 knockdown cells, suggesting that NEDD4 might function in mitophagy. Furthermore, SQSTM1 is ubiquitinated by NEDD4 while LC3 functions as an activator of NEDD4 ligase activity. Taken together, our studies define an important role of NEDD4 in regulation of autophagy.
微管相关蛋白1轻链3（MAP1LC3）/轻链3（LC3）家族在自噬体的生物发生和运输中起着至关重要的作用。在本报告中，我们表明HECT家族E3泛素连接酶NEDD4与LC3相互作用，并参与自噬体的生物发生。NEDD4通过位于C2和WW2结构域之间区域的保守WXXL LC3结合基序与LC3结合。敲低NEDD4会损害饥饿或雷帕霉素诱导的自噬激活和自噬体生物发生，并导致与内质网膜标记物共定位的LC3斑点聚集。电子显微镜观察到NEDD4敲低细胞中存在巨大变形的线粒体，这表明NEDD4可能在线粒体自噬中发挥作用。此外，SQSTM1被NEDD4泛素化，而LC3作为NEDD4连接酶活性的激活剂。综上所述，我们的研究确定了NEDD4在自噬调节中的重要作用。
