title: EVI1 acts as an inducible negative-feedback regulator of NF-κB by inhibiting p65 acetylation.
abstract: 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.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Xiangbin
authors.initials: X
authors.lastname: Xu
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Woo
authors.forename: Rachel R
authors.initials: RR
authors.lastname: Steere
authors.forename: Byung Cheol
authors.initials: BC
authors.lastname: Lee
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Huang
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Jinjiang
authors.initials: J
authors.lastname: Pang
authors.forename: Jae Hyang
authors.initials: JH
authors.lastname: Lim
authors.forename: Haidong
authors.initials: H
authors.lastname: Xu
authors.forename: Wenhong
authors.initials: W
authors.lastname: Zhang
authors.forename: Anuhya S
authors.initials: AS
authors.lastname: Konduru
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Michael T
authors.initials: MT
authors.lastname: Cheeseman
authors.forename: Steve D M
authors.initials: SD
authors.lastname: Brown
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D025461:Feedback, Physiological / Q000502:physiology*; D006192:Haemophilus Infections / Q000276:immunology / Q000378:metabolism; D006193:Haemophilus influenzae / Q000276:immunology; D047468:Immunoprecipitation; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000276:immunology; D034622:RNA Interference; D060888:Real-Time Polymerase Chain Reaction; D051996:Transcription Factor RelA / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C499305:Mecom protein, mouse; D016328:NF-kappa B; D000090063:Proto-Oncogene Mas; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha