Journal
CELLULAR SIGNALLING
Volume 24, Issue 6, Pages 1141-1149Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2012.01.021
Keywords
Arteriosclerosis; Leukocytes; Lipoproteins; Molecular biology; Signal transduction
Categories
Funding
- Deutsche Forschungsgemeinschaft [Br 999, SFB 815, FOG 784]
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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 IFN beta expression occurs. To understand molecular mechanisms how oxLDL inhibits LPS-induced IFN beta expression in macrophage-derived foam cells, we analyzed the impact of oxLDL on signaling pathways upstream of IFN beta expression. We identified mono-ubiquitination of TANK (TRAF family member-associated NF kappa B activator), a scaffold protein of the TRIF (TIR-domain-containing adapter-inducing IFN beta)-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. (c) 2012 Elsevier Inc. All rights reserved.
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