Negative Feedback Regulation of NF-κB Action by CITED2 in the Nucleus

Abstract

NF-κB is a family of important transcription factors that modulate immunity, development, inflammation, and cancer. The biological activity of NF-κB is subjected to various spatial and temporal regulations. Bioinformatics analysis predicts that CITED2 is topologically close to NF-κB in the protein interaction networks. In this study, we show that ectopic expression or knockdown of CITED2 attenuates or potentiates, respectively, the expression of NF-κB–responsive genes. Mechanistically, CITED2 constitutively localizes inside the nucleus and interacts specifically with the coactivator p300. This prevents p65 from binding to p300, impairs p65 acetylation, and attenuates p65 binding to its cognate promoters. Furthermore, LPS induces CITED2 expression via NF-κB in macrophages. CITED2 sensitizes cells to TNF-α–induced apoptosis. Collectively, this study identifies CITED2 as a novel regulator of NF-κB in the nucleus, which reveals a negative feedback mechanism for NF-κB signaling.

GILZ Overexpression Inhibits Endothelial Cell Adhesive Function through Regulation of NF-κB and MAPK Activity

“…The exact mechanism through which GILZ impacts on DNA binding remains unclear. However, it is known that posttranslational modifications (e.g., phosphorylation and acetylation) of NF-kB are absolutely required for its optimal transcriptional activity (36)(37)(38), and, in many cases, these posttranslational modifications are able to alter transcriptional activity without affecting nuclear translocation (39)(40)(41).…”

FBXL5 modulates HIF-1α transcriptional activity by degradation of CITED2

“…We demonstrated that Introduction 47 Hypoxia inducible factors (HIF) 1 1 and 2 are crucial to mediate 48 the cellular adaptation in response to hypoxia [1]. HIF-1 and HIF-2 49 are heterodimers formed by the oxygen-sensitive subunits, HIF-1a 50 and HIF-2a, and a constitutive subunit referred to as HIF-1b or 51 Arnt1. Under normoxic conditions, the oxygen, 2-oxoglutarate and 52 iron-dependent prolyl hydroxylases (PHDs) catalyse the hydroxyla- 53 tion of two key proline residues present in the oxygen-dependent 54 degradation domain (ODDD) of HIF-1a and HIF-2a, promoting their 55 recognition by the von Hippel-Lindau protein (pVHL) E3 ligase and 56 their subsequent degradation by the proteasome [2].…”

“…665 Of particular interest, yeast two-hybrid screenings have pointed 666 out a potential interaction between FBXL5 and p300 in the human 667 liver protein network [47]. tion might also indirectly affect the acetylation process of tran-683 scription factors by CBP/p300, such as p53 and NF-jB [49,50]. 684 Since cellular iron and oxygen deprivation destabilizes FBXL5 and 685 promotes its own degradation by the proteasome [27,28], the 686 interaction between CITED2 and the CH1 domain of CBP/p300 687 might also be modulated by the cellular availability of iron and 688 oxygen.…”

UXT-V1 Facilitates the Formation of MAVS Antiviral Signalosome on Mitochondria

“…Bone marrow-derived macrophages (BMDMs) were obtained, as described previously (29). BMDMs were harvested after ∼6∼10 d and recultured in 12-well plates for small interfering RNA (siRNA) transfection using lipofectamine 2000 (Invitrogen) and further experiments.…”