Keap1 facilitates p62-mediated ubiquitin aggregate clearance via autophagy.
The accumulation of ubiquitin-positive protein aggregates has been implicated in the pathogenesis of neurodegenerative diseases, heart disease and diabetes. Emerging evidence indicates that the autophagy lysosomal pathway plays a critical role in the clearance of ubiquitin aggregates, a process that is mediated by the ubiquitin binding protein p62. In addition to binding ubiquitin, p62 also interacts with LC3 and transports ubiquitin conjugates to autophagosomes for degradation. The exact regulatory mechanism of this process is still largely unknown. Here we report the identification of Keap1 as a binding partner for p62 and LC3. Keap1 inhibits Nrf2 by sequestering it in the cytosol and preventing its translocation to the nucleus and activation of genes involved in the oxidative stress response. In this study, we found that Keap1 interacts with p62 and LC3 in a stress-inducible manner, and that Keap1 colocalizes with LC3 and p62 in puromycin-induced ubiquitin aggregates. Moreover, p62 serves as a bridge between Keap1 and ubiquitin aggregates and autophagosomes. Finally, genetic ablation of Keap1 leads to the accumulation of ubiquitin aggregates, increased cytotoxicity of misfolded protein aggregates, and defective activation of autophagy. Therefore, this study assigns a novel positive role of Keap1 in upregulating p62-mediated autophagic clearance of ubiquitin aggregates.
Fan
Weiliang
W
State Key Lab of Plant Physiology and Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China.
Tang
Zaiming
Z
Chen
Dandan
D
Moughon
Diana
D
Ding
Xiaojun
X
Chen
She
S
Zhu
Muyuan
M
Zhong
Qing
Q
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001343:Autophagy; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017353:Gene Deletion; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D050356:Lipid Metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D010588:Phagosomes / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D021381:Protein Transport; D000071456:Sequestosome-1 Protein; D013312:Stress, Physiological; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C490981:Gtf2h1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D014157:Transcription Factors; D025801:Ubiquitin; D051758:Transcription Factor TFIIH