Novel splice variants of human IKK epsilon negatively regulate IKK epsilon-induced IRF3 and NF-kB activation

The inhibitor of kappa B kinase epsilon (IKK epsilon) is pivotal for an efficient innate immune response to viral infections and has been recognized as breast cancer oncogene. The antiviral function of IKKe involves activation of the transcription factors IFN regulatory factor 3 (IRF3) and NF-kappa B, thus inducing the expression of type I IFN. Here, we have identified two novel splice variants of human IKK epsilon, designated IKK epsilon-sv1 and IKK epsilon-sv2, respectively. Interestingly, RTPCR revealed quantitatively different isoform expression in PBMC from different individuals. Moreover, we found cell type-and stimulus-specific protein expression of the various splice variants. Overexpression of full-length wt IKK epsilon (IKK epsilon-wt) leads to the activation of NF-kappa B- as well as IRF3-driven luciferase reporter genes. Although none of the splice variants activates IRF3, IKK epsilon-sv1 still activates NF-kappa B, whereas IKK epsilon-sv2 is also defective in NF-kappa B activation. Both splice variants form dimers with IKKe-wt and inhibit IKK epsilon-wt-induced IRF3 signaling including the antiviral activity in a dominant-negative manner. The lack of IRF3 activation is likely caused by the failure of the splice variants to interact with the adapter proteins TANK, NAP1, and/or SINTBAD. Taken together, our data suggest alternative splicing as a novel regulatory mechanism suitable to shift the balance between different functions of IKK epsilon.