title: Toll-Like Receptor Signaling Induces Nrf2 Pathway Activation through p62-Triggered Keap1 Degradation.
abstract: Toll-like receptors (TLRs) induce inflammation and tissue repair through multiple signaling pathways. The Nrf2 pathway plays a key role in defending against the tissue damage incurred by microbial infection or inflammation-associated diseases. The critical event that mediates TLR-induced Nrf2 activation is still poorly understood. In this study, we found that lipopolysaccharide (LPS) and other Toll-like receptor (TLR) agonists activate Nrf2 signaling and the activation is due to the reduction of Keap1, the key Nrf2 inhibitor. TLR signaling-induced Keap1 reduction promoted Nrf2 translocation from the cytoplasm to the nucleus, where it activated transcription of its target genes. TLR agonists modulated Keap1 at the protein posttranslation level through autophagy. TLR signaling increased the expression of autophagy protein p62 and LC3-II and induced their association with Keap1 in the autophagosome-like structures. We also characterized the interaction between p62 and Keap1 and found that p62 is indispensable for TLR-mediated Keap1 reduction: TLR signaling had no effect on Keap1 if cells lacked p62 or if cells expressed a mutant Keap1 that could not interact with p62. Our study indicates that p62-mediated Keap1 degradation through autophagy represents a critical linkage for TLR signaling regulation of the major defense network, the Nrf2 signaling pathway.
authors.affiliation: Nanjing University School of Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Yin
authors.affiliation: Nanjing University School of Medicine, Jiangsu Key Laboratory of Molecular Medicine, Nanjing, China wangsencao@nju.edu.cn.
authors.forename: Wangsen
authors.identifier: http://orcid.org/0000-0001-6209-3482
authors.initials: W
authors.lastname: Cao
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D006360:Heat-Shock Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008070:Lipopolysaccharides; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D051193:Toll-Like Receptors