title: Peroxiredoxin-6 Negatively Regulates Bactericidal Activity and NF-κB Activity by Interrupting TRAF6-ECSIT Complex.
abstract: A TRAF6-ECSIT complex is crucial for the generation of mitochondrial reactive oxygen species (mROS) and nuclear factor-kappa B (NF-κB) activation induced by Toll-like receptor 4 (TLR4). Peroxiredoxin-6 (Prdx6) as a member of the peroxiredoxin family of antioxidant enzymes is involved in antioxidant protection and cell signaling. Here, we report on a regulatory role of Prdx6 in mROS production and NF-κB activation by TLR4. Prdx6 was translocated into the mitochondria by TLR4 stimulation and Prdx6-knockdown (Prdx6KD) THP-1 cells had increased level of mitochondrial reactive oxygen species levels and were resistant toSalmonella typhimuriuminfection. Biochemical studies revealed Prdx6 interaction with the C-terminal TRAF-C domain of TRAF6, which drove translocation into the mitochondria. Interestingly, Prdx6 competitively interacted with ECSIT to TRAF6 through its C-terminal TRAF-C domain, leading to the interruption of TRAF6-ECSIT interaction. The inhibitory effect was critically implicated in the activation of NF-κB induced by TLR4. Overexpression of Prdx6 led to the inhibition of NF-κB induced by TLR4, whereas Prdx6KDTHP-1 cells displayed enhanced production of pro-inflammatory cytokines including interleukin-6 and -1β, and the up-regulation of NF-κB-dependent genes induced by TLR4 stimulation. Taken together, the data demonstrate that Prdx6 interrupts the formation of TRAF6-ECSIT complex induced by TLR4 stimulation, leading to suppression of bactericidal activity because of inhibited mROS production in mitochondria and the inhibition of NF-κB activation in the cytoplasm.
authors.affiliation: Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine Suwon, South Korea.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Min
authors.affiliation: Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine Suwon, South Korea.
authors.forename: Sae M
authors.initials: SM
authors.lastname: Wi
authors.affiliation: Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine Suwon, South Korea.
authors.forename: Dongwoo
authors.initials: D
authors.lastname: Shin
authors.affiliation: Department of Immunology and Infectious Diseases, Department of Medicine, Harvard School of Public Health, Harvard Medical School Boston, MA, USA.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Chun
authors.affiliation: Department of Molecular Cell Biology and Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine Suwon, South Korea.
authors.forename: Ki-Young
authors.initials: KY
authors.lastname: Lee
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D054465:Peroxiredoxin VI / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism; D012475:Salmonella / Q000502:physiology; D012480:Salmonella Infections / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C518657:Ecsit protein, human; D018836:Inflammation Mediators; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D054465:Peroxiredoxin VI
keywords: ECSIT; NF-κB; TRAF6; bactericidal activity; mROS; peroxiredoxin-6