JMJD8 is a positive regulator of TNF-induced NF-κB signaling.

Kok Siong Yeo,Wan Ying Wong,Ming Cheang Tan,Chee-Kwee Ea,Yat-Yuen Lim,Chin Leng Tan,Sheng Wei Loh,Yi Lyn Lam

doi:10.1038/srep34125

Abstract

TNF-induced signaling mediates pleiotropic biological consequences including inflammation, immunity, cell proliferation and apoptosis. Misregulation of TNF signaling has been attributed as a major cause of chronic inflammatory diseases and cancer. Jumonji domain-containing protein 8 (JMJD8) belongs to the JmjC family. However, only part of the family members has been described as hydroxylase enzymes that function as histone demethylases. Here, we report that JMJD8 positively regulates TNF-induced NF-κB signaling. Silencing the expression of JMJD8 using RNA interference (RNAi) greatly suppresses TNF-induced expression of several NF-κB-dependent genes. Furthermore, knockdown of JMJD8 expression reduces RIP ubiquitination, IKK kinase activity, delays IκBα degradation and subsequently blocks nuclear translocation of p65. In addition, JMJD8 deficiency enhances TNF-induced apoptosis. Taken together, these findings indicate that JMJD8 functions as a positive regulator of TNF-induced NF-κB signaling.

Highlights

tumor necrosis factor (TNF)-induced signaling mediates pleiotropic biological consequences including inflammation, immunity, cell proliferation and apoptosis
To the best of our knowledge, this is the first report that demonstrates a functional role of JMJD8 in TNF-induced NF-κB signaling
We show that knockdown of JMJD8 expression in HEK293T cells results in reduced TNF-induced NF-κB-dependent genes expressions, IκBαdegradation and p65 nuclear translocation

Summary

Introduction

TNF-induced signaling mediates pleiotropic biological consequences including inflammation, immunity, cell proliferation and apoptosis. Jumonji domain-containing protein 8 (JMJD8) belongs to the JmjC family. We report that JMJD8 positively regulates TNF-induced NF-κB signaling. Previous studies showed that methylation of p65 at lysine 37 (K37) by a methytransferase, SET9 modulates its function[10], while acetylation of p65 at K218 and K221 inhibits IκB binding and enhances DNA binding[12], and acetylation of p65 at K122 and K123 inhibits its transcriptional activation activity[13] Most of the JmjC domain-containing proteins are hydroxylase enzymes that function as demethylases[18]. Many proteins in this family have been shown to be involved in cell development, differentiation and proliferation through regulating various signaling pathways. JMJD2C ( known as GASC1) is upregulated in squamous cell carcinoma[20] and it www.nature.com/scientificreports/

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