title: Separation of zinc-dependent and zinc-independent events during early LPS-stimulated TLR4 signaling in macrophage cells.
abstract: Free zinc is required for proper lipopolysaccharide (LPS)-stimulated signaling, but potential sites of action in the pathway have not been defined. In this work, we provide in vitro and ex vivo evidence that zinc is not required for phosphorylation or ubiquitylation of IRAK1, a kinase functioning early in the TLR4 pathway. However, degradation of ubiquitylated IRAK1 occurred via a zinc-dependent, proteasome-independent pathway. These results provide evidence of a novel site of action for zinc during TLR4-mediated inflammatory responses.
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO 65211, USA; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Petris
authors.affiliation: Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA. Electronic address: pecks@missouri.edu.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Peck
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D046988:Proteasome Endopeptidase Complex; D015032:Zinc
keywords: LPS; Macrophage; Proteasome-independent degradation; Signaling; Zinc