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

AbstractThe 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