title: The E3 ubiquitin ligase NEDD4 is an LC3-interactive protein and regulates autophagy.
abstract: 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.
authors.affiliation: a School of Medicine, Jiangsu University , Zhenjiang , China.
authors.forename: Aiqin
authors.initials: A
authors.lastname: Sun
authors.affiliation: a School of Medicine, Jiangsu University , Zhenjiang , China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wei
authors.affiliation: b Department of Biology , Susquehanna University , Selinsgrove , PA , USA.
authors.forename: Chandra
authors.initials: C
authors.lastname: Childress
authors.affiliation: c Department of Pathology , Geisinger Clinic , Danville , PA , USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Shaw
authors.affiliation: a School of Medicine, Jiangsu University , Zhenjiang , China.
authors.forename: Ke
authors.initials: K
authors.lastname: Peng
authors.affiliation: a School of Medicine, Jiangsu University , Zhenjiang , China.
authors.forename: Genbao
authors.initials: G
authors.lastname: Shao
authors.affiliation: a School of Medicine, Jiangsu University , Zhenjiang , China.
authors.forename: Wannian
authors.initials: W
authors.lastname: Yang
authors.affiliation: a School of Medicine, Jiangsu University , Zhenjiang , China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Lin
mesh_terms: D000072283:A549 Cells; D000071182:Autophagosomes / Q000378:metabolism / Q000648:ultrastructure; D001343:Autophagy; D015415:Biomarkers / Q000378:metabolism; D017124:Conserved Sequence; D004721:Endoplasmic Reticulum / Q000378:metabolism; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D000071456:Sequestosome-1 Protein / Q000378:metabolism; D013379:Substrate Specificity; D054875:Ubiquitination
chemical_list: D015415:Biomarkers; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D049452:Green Fluorescent Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases
keywords: E3 ubiquitin ligase; LC3; NEDD4; SQSTM1/p62; autophagy; ubiquitination