Asymmetric arginine dimethylation of RelA provides a repressive mark to modulate TNFα/NF-κB response
A Reintjes, JE Fuchs, L Kremser, HH Lindner… - Proceedings of the …, 2016 - pnas.org
Proceedings of the National Academy of Sciences, 2016•pnas.org
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 …
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 …
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.
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