EVI1 acts as an inducible negative-feedback regulator of NF-?B 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-?B-dependent inflammation remains unknown. In this article, we show that EVI1 negatively regulates nontypeable Haemophilus influenzae- and TNF-?-induced NF-?B-dependent inflammation in vitro and in vivo. EVI1 directly binds to the NF-?B 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-? in an NF-?B-dependent manner, thereby unveiling a novel inducible negative feedback loop to tightly control NF-?B-dependent inflammation. Thus, our study provides important insights into the novel role for EVI1 in negatively regulating NF-?B-dependent inflammation, and it may also shed light on the future development of novel anti-inflammatory strategies.

SUBMITTER: Xu X 

PROVIDER: S-EPMC3370108 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature