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

Journal of Cell Science - Tập 130 Số 22 - Trang 3839-3850 - 2017
Qiong Lin1, Qian Dai1, Hongxia Meng1, Aiqin Sun1, Wei Jing1, Ke Peng1, Chandra Childress2, Miao Chen3, Genbao Shao1, Wannian Yang1
1School of Medicine, Jiangsu University 1 , Zhenjiang 212013 , China
2Susquehanna University 2 Department of Biology , , 514 University Ave, Selinsgrove, PA 17870 , USA
3Affiliated People's Hospital, Jiangsu University 3 Department of Pathology , , Zhenjiang 212013 , China

Tóm tắt

ABSTRACT 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 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.

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