The HECT E3 ubiquitin ligase NEDD4 interacts with and ubiquitylates SQSTM1 for inclusion body autophagy
The HECT E3 ubiquitin ligase NEDD4 interacts with and ubiquitylates SQSTM1 for inclusion body autophagy
复制标题
HECT E3 泛素连接酶 NEDD4 与 SQSTM1 相互作用并泛素化，以实现包涵体自噬。
DOI：
10.1242/jcs.207068
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发表时间：
2017-11-15
影响因子：
4
通讯作者：
Yang, Wannian
中科院分区：
文献类型：
--
作者：
Lin, Qiong;Dai, Qian;Yang, Wannian
我们之前的研究表明，HECT E3泛素连接酶NEDD4与LC3相互作用，是饥饿和雷帕霉素诱导的自噬激活所必需的。在这里，我们报道NEDD4通过其HECT结构域直接与SQSTM1结合，并使SQSTM1多泛素化。这种泛素化是通过K63偶联进行的，不参与蛋白酶体降解。突变分析表明NEDD4与SQSTM1的PB1结构域相互作用并泛素化。NEDD4缺失或NEDD4连接酶缺陷突变体的过表达诱导了异常增大的sqstm1阳性包涵体的积累，这些包涵体与内质网（ER）标记CANX共定位，表明泛素化在包涵体自噬体中sqstm1介导的生物生成过程中起作用。综上所述，我们的研究表明NEDD4是一种自噬性E3泛素连接酶，可使SQSTM1泛素化，促进SQSTM1介导的包涵体自噬。
Our previous studies have shown that the HECT E3 ubiquitin ligase NEDD4 interacts with LC3 and is required for starvation and rapamycininduced activation of autophagy. Here, we report that NEDD4 directly binds to SQSTM1 via its HECT domain and polyubiquitylates SQSTM1. This ubiquitylation is through K63 conjugation and is not involved in proteasomal degradation. Mutational analysis indicates that NEDD4 interacts with and ubiquitylates the PB1 domain of SQSTM1. Depletion of NEDD4 or overexpression of the ligase-defective mutant of NEDD4 induced accumulation of aberrant enlarged SQSTM1-positive inclusion bodies that are co-localized with the endoplasmic reticulum(ER) marker CANX, suggesting that the ubiquitylation functions in the SQSTM1-mediated biogenic process in inclusion body autophagosomes. Taken together, our studies show that NEDD4 is an autophagic E3 ubiquitin ligase that ubiquitylates SQSTM1, facilitating SQSTM1-mediated inclusion body autophagy.