title: TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain.
abstract: New evidence indicates the involvement of protein degradation dysfunctions in neurodegeneration, innate immunity response and alcohol hepatotoxicity. We recently demonstrated that ethanol increases brain proinflammatory mediators and causes brain damage by activating Toll-like receptor 4 (TLR4) signaling in glia. However, it is uncertain if the ubiquitin-proteasome and autophagy-lysosome pathways are involved in ethanol-induced brain damage and whether the TLR4 response is implicated in proteolytic processes. Using the cerebral cortex of WT and TLR4-knockout mice with and without chronic ethanol treatment, we demonstrate that ethanol induces poly-ubiquitinated proteins accumulation and promotes immunoproteasome activation by inducing the expression of β2i, β5i and PA28α, although it decreases the 20S constitutive proteasome subunits (α2, β5). Ethanol also upregulates mTOR phosphorylation, leading to a downregulation of the autophagy-lysosome pathway (ATG12, ATG5, cathepsin B, p62, LC3) and alters the volume of autophagic vacuoles. Notably, mice lacking TLR4 receptors are protected against ethanol-induced alterations in protein degradation pathways. In summary, the present results provide the first evidence demonstrating that chronic ethanol treatment causes proteolysis dysfunctions in the mouse cerebral cortex and that these events are TLR4 dependent. These findings could provide insight into the mechanisms underlying ethanol-induced brain damage.
authors.affiliation: Department of Cellular Pathology, Centro de Investigación Príncipe Felipe, C/Eduardo Primo Yúfera 3, Valencia 46012, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Pla
authors.affiliation: Department of Cellular Pathology, Centro de Investigación Príncipe Felipe, C/Eduardo Primo Yúfera 3, Valencia 46012, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Pascual
authors.affiliation: Section of Biology and Cellular Pathology, Centro Investigación Hospital La Fe, Avda. de Campanar 114, Valencia 46015, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Renau-Piqueras
authors.affiliation: Department of Cellular Pathology, Centro de Investigación Príncipe Felipe, C/Eduardo Primo Yúfera 3, Valencia 46012, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Guerri
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; D002401:Cathepsin B / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D000431:Ethanol / Q000633:toxicity*; D008247:Lysosomes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000276:immunology / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism; D054875:Ubiquitination
chemical_list: C491971:Atg12 protein, mouse; C495773:Atg5 protein, mouse; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; C490981:Gtf2h1 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D061988:Proteasome Inhibitors; D047428:Protein Kinase Inhibitors; D011506:Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D000431:Ethanol; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D002401:Cathepsin B; C533915:Ctsb protein, mouse; C569717:PSMB2 protein, mouse; D046988:Proteasome Endopeptidase Complex; C478802:Psmb5 protein, mouse; C486213:Psme1 protein, mouse