SETD6 (SET domain-containing protein 6) is a 473 amino acid protein that belongs to the SETD6 family. Containing one SET domain, SETD6 is structurally similar to the Rubisco large subunit methyltransferase. SETD6 is a proteinlysine N-methyltransferase that specifically monomethylates “Lys-310” of the NF?B p65 subunit of NF?B complex, leading to down-regulate NF?B transcription factor activity. SETD6-mediated methylation renders NF?B p65 inert and attenuates NF?B p65-driven transcriptional programs, including inflammatory responses in primary immune cells. The SETD6-initiated lysine-methylation signaling cascade acts to restrain activation of NF?B-mediated inflammatory responses in diverse cell types.