Kruppel-like Factor 6 Is a Co-activator of NF- κB That Mediates p65-dependent Transcription of Selected Downstream Genes

Background: Transcription factor NF-B is involved in various biological processes and regulated at multiple levels. Results: KLF6 modulates NF-B-mediated transcription by promoting binding of p65 to promoters of downstream genes. Conclusion: KLF6 is a co-activator of NF-B-mediated transcription of selected downstream genes. Significance: Our study reveals a new regulatory mechanism for NF-B-mediated transcriptional activation in the nucleus. The transcription factor NF-B plays a pivotal role in a broad range of physiological and pathological processes, including development, inflammation, and immunity. How NF-B integrates activating signals to expression of specific sets of target genes is of great interest. Here, we identified Kruppel-like factor 6 (KLF6) as a co-activator of NF-B after TNF and IL-1 stimulation. Overexpression of KLF6 enhanced TNF- and IL-1-induced activation of NF-B and transcription of a subset of downstream genes, whereas knockdown of KLF6 had opposite effects. KLF6 interacted with p65 in the nucleus and bound to the promoters of target genes. Upon IL-1 stimulation, KLF6 was recruited to promoters of a subset of NF-B target genes in a p65-dependent manner, which was in turn required for the optimal binding of p65 to the target gene promoters. Our findings thus identified KLF6 as a previously unknown but essential co-activator of NF-B and provided new insight into the molecular regulation of p65-dependent gene expression.