The transcription factor nuclear factor kappa;B (NF-kappa;B) plays a pivotal role in immune and inflammatory responses. Activation of NF-kappa;B requires the activity of IKK, a kinase complex that contains two catalytic subunits, IKKalpha; and IKKbeta;, and a regulatory subunit IKKgamma;. To understand how IKK activity is regulated, we searched for IKKgamma;-interacting proteins by the yeast two-hybrid system. These screenings identified CSN3, a component of the COP9 signalsome, as a protein specifically interacting with IKKgamma;. Overexpression of CSN3 inhibits NF-kappa;B activation triggered by tumor necrosis factor (TNF), but not interleukin-1 (IL-1). Moreover, overexpression of CSN3 also inhibits NF-kappa;B 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-kappa;B activation pathways.
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