CSN3 interacts with IKKγ and inhibits TNF‐ but not IL‐1‐induced NF‐κB activation

Abstract

The transcription factor nuclear factor κB (NF‐κB) plays a pivotal role in immune and inflammatory responses. Activation of NF‐κB requires the activity of IKK, a kinase complex that contains two catalytic subunits, IKKα and IKKβ, and a regulatory subunit IKKγ. To understand how IKK activity is regulated, we searched for IKKγ‐interacting proteins by the yeast two‐hybrid system. These screenings identified CSN3, a component of the COP9 signalsome, as a protein specifically interacting with IKKγ. Overexpression of CSN3 inhibits NF‐κB activation triggered by tumor necrosis factor (TNF), but not interleukin‐1 (IL‐1). Moreover, overexpression of CSN3 also inhibits NF‐κB activation triggered by proteins involved in TNF signaling, including TNF‐R1, TRAF2, RIP, and NIK, but not by TRAF6, a protein involved in IL‐1 signaling. These data suggest that CSN3 is a specific negative regulator of TNF‐ but not IL‐1‐induced NF‐κB activation pathways.