The Deubiquitinase USP17 Regulates the Stability and Nuclear Function of IL-33.

Yingmeng Ni,Huihui Song,Bin Li,Chen Chen,Lianqin Tao,Zhiyuan Li,Guochao Shi,Miranda Piccioni,Jia Nie,Yayi Gao

doi:10.3390/ijms161126063

Abstract

IL-33 is a new member of the IL-1 family cytokines, which is expressed by different types of immune cells and non-immune cells. IL-33 is constitutively expressed in the nucleus, where it can act as a transcriptional regulator. So far, no direct target for nuclear IL-33 has been identified, and the regulation of IL-33 nuclear function remains largely unclear. Here, we report that the transcription of type 2 inflammatory cytokine IL-13 is positively regulated by nuclear IL-33. IL-33 can directly bind to the conserved non-coding sequence (CNS) before the translation initiation site in the IL13 gene locus. Moreover, IL-33 nuclear function and stability are regulated by the enzyme ubiquitin-specific protease 17 (USP17) through deubiquitination of IL-33 both at the K48 and at the K63 sites. Our data suggest that IL13 gene transcription can be directly activated by nuclear IL-33, which is negatively regulated by the deubiquitinase USP17.

Highlights

Interleukin-33 (IL-33) was initially discovered as a nuclear factor in endothelial cells and named for this reason NF-HEV [1]
Our study has showed the existence of ubiquitination of IL-33, which can be regulated by deubiquitinase in human embryonic kidney (HEK) 293T cells [10]
Expression vectors encoding Flag-tagged IL-33 and His-tagged ubiquitin were co-transfected into human embryonic kidney (HEK) 293T cells for a ubiquitin pull-down assay

Summary

Introduction

Interleukin-33 (IL-33) was initially discovered as a nuclear factor in endothelial cells and named for this reason NF-HEV (nuclear factor from high endothelial venules) [1]. Afterwards, it was identified as a novel member of the IL-1 cytokine family, binding to the orphan IL-1 receptor family member ST2 ( known as IL-1RL1) [2]. IL-33 is involved in the regulation of transcription. Another study suggests that nuclear IL-33 could bind to the promoter region of p65, positively regulating its transcription in endothelial cells [9]

Methods

Results

Conclusion