ZC3H11A loss of function enhances NF-κB signaling through defective IκBα protein expression

ZC3H11A is a cellular protein associated with the transcription export (TREX) complex that is induced during heat-shock. Several nuclear-replicating viruses exploit the mRNA export mechanism of ZC3H11A protein for their efficient replication. Here we show that ZC3H11A protein plays a role in regulation of NF-kappa B signal transduction. Depletion of ZC3H11A resulted in enhanced NF-kappa B mediated signaling, with upregulation of numerous innate immune related mRNAs, including IL-6 and a large group of interferon-stimulated genes. IL-6 upregulation in the absence of the ZC3H11A protein correlated with an increased NF-kappa B transcription factor binding to the IL-6 promoter and decreased IL-6 mRNA decay. The enhanced NF-kappa B signaling pathway in ZC3H11A deficient cells correlated with a defect in I kappa B alpha inhibitory mRNA and protein accumulation. Upon ZC3H11A depletion The I kappa B alpha mRNA was retained in the cell nucleus resulting in failure to maintain normal levels of the cytoplasmic I kappa B alpha mRNA and protein that is essential for its inhibitory feedback loop on NF-kappa B activity. These findings indicate towards a previously unknown mechanism of ZC3H11A in regulating the NF-kappa B pathway at the level of IkB alpha mRNA export.