title: Pattern recognition scavenger receptor CD204 attenuates Toll-like receptor 4-induced NF-kappaB activation by directly inhibiting ubiquitination of tumor necrosis factor (TNF) receptor-associated factor 6.
abstract: The collaboration and cross-talk between different classes of innate pattern recognition receptors are crucial for a well coordinated inflammatory response and host defense. Here we report a previously unrecognized role of scavenger receptor A (SRA; also known as CD204) as a signaling regulator in the context of Toll-like receptor 4 (TLR4) activation. We show that SRA/CD204 deficiency leads to greater sensitivity to LPS-induced endotoxic shock. SRA/CD204 down-regulates inflammatory gene expression in dendritic cells by suppressing TLR4-induced activation of the transcription factor NF-κB. For the first time, we demonstrate that SRA/CD204 executes its regulatory functions by directly interacting with the TRAF-C domain of TNF receptor-associated factor 6 (TRAF6), resulting in inhibition of TRAF6 dimerization and ubiquitination. The attenuation of NF-κB activity by SRA/CD204 is independent of its ligand-binding domain, indicating that the signaling-regulatory feature of SRA/CD204 can be uncoupled from its conventional endocytic functions. Collectively, we have identified the molecular linkage between SRA/CD204 and the TLR4 signaling pathways, and our results reveal a novel mechanism by which a non-TLR pattern recognition receptor restricts TLR4 activation and consequent inflammatory response.
authors: Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
authors: Xiaofei
authors: X
authors: Yu
authors: Huanfa
authors: H
authors: Yi
authors: Chunqing
authors: C
authors: Guo
authors: Daming
authors: D
authors: Zuo
authors: Yanping
authors: Y
authors: Wang
authors: Hyung L
authors: HL
authors: Kim
authors: John R
authors: JR
authors: Subjeck
authors: Xiang-Yang
authors: XY
authors: Wang
mesh_terms: D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D055503:Protein Multimerization / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D051117:Scavenger Receptors, Class A / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects / Q000235:genetics / Q000276:immunology*
chemical_list: D008070:Lipopolysaccharides; C495139:MSR1 protein, human; C495140:Msr1 protein, mouse; D016328:NF-kappa B; D051117:Scavenger Receptors, Class A; C495345:TLR4 protein, human; D048029:TNF Receptor-Associated Factor 6; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4