title: OxLDL inhibits LPS-induced IFNβ expression by Pellino3- and IRAK1/4-dependent modification of TANK.
abstract: In atherosclerosis macrophages contribute to disease progression. After infiltrating atherosclerotic lesions they accumulate oxLDL (oxidized low density lipoproteins) and differentiate into foam cells. During this process inhibition of TLR4 (Toll-like receptor 4)-dependent IFNβ expression occurs. To understand molecular mechanisms how oxLDL inhibits LPS-induced IFNβ expression in macrophage-derived foam cells, we analyzed the impact of oxLDL on signaling pathways upstream of IFNβ expression. We identified mono-ubiquitination of TANK (TRAF family member-associated NFκB activator), a scaffold protein of the TRIF (TIR-domain-containing adapter-inducing IFNβ)-dependent TLR4-signaling cascade. Modified TANK inhibits recruitment of TBK1 (TANK-binding kinase 1) to TRAF3 (TNF receptor associated factor 3) and the subsequent activation of the transcription factor IRF3 (interferon regulatory factor 3). OxLDL stimulates TANK mono-ubiquitination by subsequent activation of IRAK1/4 (interleukin-1 receptor-associated kinases 1 and 4) and Pellino3 downstream of SR-A1 (scavenger receptor-A1). Our observations highlight the regulatory impact of IRAK1/4 and Pellino3 on the TRIF-dependent TLR4-signaling cascade, which might be of general importance for disease conditions associated with macrophage pathologies such as atherosclerosis.
authors.affiliation: Institute of Biochemistry I/ZAFES, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Tzieply
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Kuhn
authors.forename: Daniel
authors.initials: D
authors.lastname: Morbitzer
authors.forename: Dmitry
authors.initials: D
authors.lastname: Namgaladze
authors.forename: Annika
authors.initials: A
authors.lastname: Heeg
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
authors.forename: Andreas
authors.initials: A
authors.lastname: von Knethen
authors.forename: Liselotte E
authors.initials: LE
authors.lastname: Jensen
authors.forename: Bernhard
authors.initials: B
authors.lastname: Brüne
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D016899:Interferon-beta / Q000235:genetics* / Q000276:immunology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D008077:Lipoproteins, LDL / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; C484406:TANK protein, human; C099252:oxidized low density lipoprotein; D016899:Interferon-beta; C503915:PELI3 protein, human; D044767:Ubiquitin-Protein Ligases; D053592:Interleukin-1 Receptor-Associated Kinases