5 years ago

The HECT E3 ubiquitin ligase NEDD4 interacts with and ubiquitinates SQSTM1 for inclusion body autophagy.

Childress, Meng, Chen, Wei, Shao, Lin, Sun, Peng, Dai, Yang
Our previous studies have shown that the HECT E3 ubiquitin ligase NEDD4 interacts with LC3 and is required for starvation and rapamycin-induced activation of autophagy. Here we report that NEDD4 directly binds to SQSTM1 via its HECT domain and poly-ubiquitinates SQSTM1. This ubiquitination is through K63 conjugation and not involved in proteasomal degradation. Mutational analysis indicates that NEDD4 interacts with and ubiquitinates 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 ubiquitination functions in the SQSTM1-mediated biogenic process of inclusion body autophagosomes. Taken together, our studies have shown that NEDD4 is an autophagic E3 ubiquitin ligase that ubiquitinates SQSTM1 and facilitating the SQSTM1-mediated inclusion body autophagy.

Publisher URL: http://doi.org/10.1242/jcs.207068

DOI: 10.1242/jcs.207068

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