EVI1 acts as an inducible negative-feedback regulator of NF-κB by inhibiting p65 acetylation

• Published in: The Journal of immunology (1950) 2012-06, Vol.188 (12), p.6371-6380
• Main Authors: Xu, Xiangbin, Woo, Chang-Hoon, Steere, Rachel R, Lee, Byung Cheol, Huang, Yuxian, Wu, Jing, Pang, Jinjiang, Lim, Jae Hyang, Xu, Haidong, Zhang, Wenhong, Konduru, Anuhya S, Yan, Chen, Cheeseman, Michael T, Brown, Steve D M, Li, Jian-Dong
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Blotting, Western; Chromatin Immunoprecipitation; DNA-Binding Proteins - immunology; DNA-Binding Proteins - metabolism; Electrophoretic Mobility Shift Assay; Feedback, Physiological - physiology; Haemophilus Infections - immunology; Haemophilus Infections - metabolism; Haemophilus influenzae; Haemophilus influenzae - immunology; Immunoprecipitation; Inflammation - immunology; Inflammation - metabolism; MDS1 and EVI1 Complex Locus Protein; Mice; Mice, Mutant Strains; NF-kappa B - immunology; NF-kappa B - metabolism; Proto-Oncogene Mas; Proto-Oncogenes - immunology; Real-Time Polymerase Chain Reaction; RNA Interference; Transcription Factor RelA - immunology; Transcription Factor RelA - metabolism; Transcription Factors - immunology; Transcription Factors - metabolism; Transfection; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1103527

Inflammation is a hallmark of many important human diseases. Appropriate inflammation is critical for host defense; however, an overactive response is detrimental to the host. Thus, inflammation must be tightly regulated. The molecular mechanisms underlying the tight regulation of inflammation remain largely unknown. Ecotropic viral integration site 1 (EVI1), a proto-oncogene and zinc finger transcription factor, plays important roles in normal development and leukemogenesis. However, its role in regulating NF-κB-dependent inflammation remains unknown. In this article, we show that EVI1 negatively regulates nontypeable Haemophilus influenzae- and TNF-α-induced NF-κB-dependent inflammation in vitro and in vivo. EVI1 directly binds to the NF-κB p65 subunit and inhibits its acetylation at lysine 310, thereby inhibiting its DNA-binding activity. Moreover, expression of EVI1 itself is induced by nontypeable Haemophilus influenzae and TNF-α in an NF-κB-dependent manner, thereby unveiling a novel inducible negative feedback loop to tightly control NF-κB-dependent inflammation. Thus, our study provides important insights into the novel role for EVI1 in negatively regulating NF-κB-dependent inflammation, and it may also shed light on the future development of novel anti-inflammatory strategies.