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NF-κB transcription factors are crucial regulators of inflammation, immunity, stress responses, and cell differentiation. Many studies have demonstrated that ubiquitination of IκB kinase γ (IKKγ), a regulatory subunit of IKK, is instrumental in the activation of IKK and NF-κB. We and others previously identified EGLN3, a member of a family of prolyl hydroxylases, as a negative regulator of the NF-κB pathway. Here we report that EGLN3, but not EGLN1 or -2, interacts with and inhibits K63-linked ubiquitination of IKKγ. The effect appears to be related to inhibition of IKKγ ubiquitination mediated by cIAP1 rather than to stimulation of IKKγ deubiquitination by the deubiquitinases A20 and CYLD (cylindromatosis). EGLN3 does not affect the protein levels of cIAP1 or its E2 ubiquitin-conjugating enzymes UbcH5 and Ubc13. EGLN3 hydroxylase activity is not responsible for its effect on IKKγ ubiquitination and NF-κB signaling. Instead, interaction with IKKγ is required for the ability of EGLN3 to inhibit IKKγ ubiquitination and IKK–NF-κB signaling. EGLN3 competes with cIAP1 for IKKγ binding, leading to inhibition of cIAP1-IKKγ interaction, IKKγ ubiquitination, and IKK–NF-κB signaling. This study provides novel insights into EGLN3 function and sheds new light on the regulation of IKKγ ubiquitination and NF-κB.

EGLN3 Inhibition of NF-κB Is Mediated by Prolyl Hydroxylase-Independent Inhibition of IκB Kinase γ Ubiquitination