title: Dynamic Arginine Methylation of Tumor Necrosis Factor (TNF) Receptor-associated Factor 6 Regulates Toll-like Receptor Signaling.
abstract: Arginine methylation is a common post-translational modification, but its role in regulating protein function is poorly understood. This study demonstrates that, TNF receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase involved in innate immune signaling, is regulated by reversible arginine methylation in a range of primary and cultured cells. Under basal conditions, TRAF6 is methylated by the methyltransferase PRMT1, and this inhibits its ubiquitin ligase activity, reducing activation of toll-like receptor signaling. In response to toll-like receptor ligands, TRAF6 is demethylated by the Jumonji domain protein JMJD6. Demethylation is required for maximal activation of NF-κB. Loss of JMJD6 leads to reduced response, and loss of PRMT1 leads to basal pathway activation with subsequent desensitization to ligands. In human primary cells, variations in the PRMT1/JMJD6 ratio significantly correlate with TRAF6 methylation, basal activation of NF-κB, and magnitude of response to LPS. Reversible arginine methylation of TRAF6 by the opposing effects of PRMT1 and JMJD6 is, therefore, a novel mechanism for regulation of innate immune pathways.
authors.affiliation: From the Department of Internal Medicine.
authors.forename: Irina
authors.initials: I
authors.lastname: Tikhanovich
authors.affiliation: From the Department of Internal Medicine.
authors.forename: Sudhakiranmayi
authors.initials: S
authors.lastname: Kuravi
authors.affiliation: Department of Biochemistry and Molecular Biology, and.
authors.forename: Antonio
authors.initials: A
authors.lastname: Artigues
authors.affiliation: Department of Biochemistry and Molecular Biology, and.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Villar
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas Medical Center, Kansas City, Kansas 66160.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dorko
authors.affiliation: Department of Surgery.
authors.forename: Atta
authors.initials: A
authors.lastname: Nawabi
authors.affiliation: From the Department of Internal Medicine.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Roberts
authors.affiliation: From the Department of Internal Medicine, sweinman@kumc.edu.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Weinman
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008297:Male; D008745:Methylation; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D016328:NF-kappa B; D012097:Repressor Proteins; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D001120:Arginine; C498707:JMJD6 protein, human; D056484:Jumonji Domain-Containing Histone Demethylases; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D044767:Ubiquitin-Protein Ligases; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: Jumonji domain-containing protein 6; TNF receptor associated factor (TRAF); arginine methylation; endotoxin; hepatocyte; innate immunity; macrophage; post-translational modification; protein arginine methyltransferase; toll-like receptor (TLR)