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

• Published in: The Journal of biological chemistry 2014-05, Vol.289 (18), p.12876-12885
• Main Authors: Zhang, Yu, Lei, Cao-Qi, Hu, Yun-Hong, Xia, Tian, Li, Mi, Zhong, Bo, Shu, Hong-Bing
• Format: Article
• Language: English
• Subjects: Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - genetics; Apoptosis - drug effects; Apoptosis - genetics; Blotting, Western; Cell Nucleus - metabolism; DNA-binding Protein; Gene Expression Regulation - drug effects; HCT116 Cells; HEK293 Cells; Humans; Interleukin; Interleukin-1beta - pharmacology; Kruppel-like factor (KLF); Kruppel-Like Factor 6; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB (NF-κB); Promoter Regions, Genetic - genetics; Protein Binding - drug effects; Protein Binding - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction; Transcription; Transcription Factor RelA - genetics; Transcription Factor RelA - metabolism; Transcription, Genetic; Tumor Necrosis Factor (TNF); Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.535831

The transcription factor NF-κB plays a pivotal role in a broad range of physiological and pathological processes, including development, inflammation, and immunity. How NF-κB integrates activating signals to expression of specific sets of target genes is of great interest. Here, we identified Krüppel-like factor 6 (KLF6) as a co-activator of NF-κB after TNFα and IL-1β stimulation. Overexpression of KLF6 enhanced TNFα- and IL-1β-induced activation of NF-κB 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-1β stimulation, KLF6 was recruited to promoters of a subset of NF-κB 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-κB and provided new insight into the molecular regulation of p65-dependent gene expression. Transcription factor NF-κB is involved in various biological processes and regulated at multiple levels. KLF6 modulates NF-κB-mediated transcription by promoting binding of p65 to promoters of downstream genes. KLF6 is a co-activator of NF-κB-mediated transcription of selected downstream genes. Our study reveals a new regulatory mechanism for NF-κB-mediated transcriptional activation in the nucleus.