title: Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response.
abstract: Nuclear factor kappa B (NF-κB) is an inducible transcription factor that plays critical roles in immune and stress responses and is often implicated in pathologies, including chronic inflammation and cancer. Although much has been learned about NF-κB-activating pathways, the specific repression of NF-κB is far less well understood. Here we identified the type I protein arginine methyltransferase 1 (PRMT1) as a restrictive factor controlling TNFα-induced activation of NF-κB. PRMT1 forms a cellular complex with NF-κB through direct interaction with the Rel homology domain of RelA. We demonstrate that PRMT1 methylates RelA at evolutionary conserved R30, located in the DNA-binding L1 loop, which is a critical residue required for DNA binding. Asymmetric R30 dimethylation inhibits the binding of RelA to DNA and represses NF-κB target genes in response to TNFα. Molecular dynamics simulations of the DNA-bound RelA:p50 predicted structural changes in RelA caused by R30 methylation or a mutation that interferes with the stability of the DNA-NF-κB complex. Our findings provide evidence for the asymmetric arginine dimethylation of RelA and unveil a unique mechanism controlling TNFα/NF-κB signaling.
authors.affiliation: Institute of Biochemistry, University of Innsbruck, A-6020 Innsbruck, Austria;
authors.forename: Anja
authors.initials: A
authors.lastname: Reintjes
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, A-6020 Innsbruck, Austria; Center for Molecular Biosciences, University of Innsbruck, A-6020 Innsbruck, Austria;
authors.forename: Julian E
authors.initials: JE
authors.lastname: Fuchs
authors.affiliation: Division of Clinical Biochemistry Biocenter, Medical University of Innsbruck, A-6020 Innsbruck, Austria;
authors.forename: Leopold
authors.initials: L
authors.lastname: Kremser
authors.affiliation: Division of Clinical Biochemistry Biocenter, Medical University of Innsbruck, A-6020 Innsbruck, Austria;
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Lindner
authors.affiliation: Institute of General, Inorganic and Theoretical Chemistry, University of Innsbruck, A-6020 Innsbruck, Austria; Center for Molecular Biosciences, University of Innsbruck, A-6020 Innsbruck, Austria;
authors.forename: Klaus R
authors.initials: KR
authors.lastname: Liedl
authors.affiliation: Division of Cell Biology, Biocenter, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
authors.forename: Lukas A
authors.initials: LA
authors.lastname: Huber
authors.affiliation: Division of Cell Biology, Biocenter, Medical University of Innsbruck, A-6020 Innsbruck, Austria Taras.Valovka@i-med.ac.at.
authors.forename: Taras
authors.initials: T
authors.lastname: Valovka
mesh_terms: D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D056004:Molecular Dynamics Simulation; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C498143:RELA protein, human; C498144:Rela protein, mouse; D012097:Repressor Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; C073701:Nfkb1 protein, mouse; C018524:N,N-dimethylarginine; D001120:Arginine; C099988:PRMT1 protein, human; C546338:Prmt1 protein, mouse; D011484:Protein-Arginine N-Methyltransferases
keywords: NF-κB; TNFα; arginine methylation; genes