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J Biol Chem. 2015 Sep 4;290(36):22236-49. doi: 10.1074/jbc.M115.653543. Epub 2015 Jul 28.

Dynamic Arginine Methylation of Tumor Necrosis Factor (TNF) Receptor-associated Factor 6 Regulates Toll-like Receptor Signaling.

Author information

1
From the Department of Internal Medicine.
2
Department of Biochemistry and Molecular Biology, and.
3
Department of Pharmacology and Toxicology, University of Kansas Medical Center, Kansas City, Kansas 66160.
4
Department of Surgery.
5
From the Department of Internal Medicine, sweinman@kumc.edu.

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.

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)

PMID:
26221041
PMCID:
PMC4571974
DOI:
10.1074/jbc.M115.653543
[Indexed for MEDLINE]
Free PMC Article

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