title: Nrf2-mediated induction of p62 controls Toll-like receptor-4-driven aggresome-like induced structure formation and autophagic degradation.
abstract: Toll-like receptors (TLRs) play a crucial role in several innate immune responses by regulating autophagy, but little is known about how TLR signaling controls autophagy. Here we demonstrate that p62/SQSTM1 is required for TLR4-mediated autophagy, which we show as selective autophagy of aggresome-like induced structures (ALIS). Treatment with LPS or Escherichia coli induced LC3(+) dot-like structures, and their assembly, but not lysosomal degradation, occurred independently of classic autophagic machinery. Microscopic and ultrastructural analyses showed that p62 is a component of the induced LC3(+) dots and these TLR4-induced p62(+) structures resemble ALIS. The levels of p62 mRNA and protein were increased in TLR4-activated cells and knockdown of p62 suppressed the ALIS formation and LC3-II conversion. The accumulation of p62 and ALIS required activation of Nrf2 by reactive oxygen species-p38 axis-dependent TLR4/MyD88 signaling, suggesting a link between innate immune and oxidative-stress responses. These findings indicate that TLR4-driven induction of p62 plays an essential role in the formation and the autophagic degradation of ALIS, which might be critical for regulating host defense.
authors.affiliation: Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Fujita
authors.forename: Daisuke
authors.initials: D
authors.lastname: Maeda
authors.forename: Qi
authors.initials: Q
authors.lastname: Xiao
authors.forename: Srinivasa M
authors.initials: SM
authors.lastname: Srinivasula
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D002460:Cell Line; D002478:Cells, Cultured; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071456:Sequestosome-1 Protein; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502661:Atg7 protein, mouse; D006360:Heat-Shock Proteins; D008070:Lipopolysaccharides; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D053594:Myeloid Differentiation Factor 88; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D051197:Toll-Like Receptor 4; D049452:Green Fluorescent Proteins; D000071193:Autophagy-Related Protein 7