Polycomb chromobox Cbx2 enhances antiviral innate immunity by promoting Jmjd3-mediated demethylation of H3K27 at the Ifnb promoter

Donghao Sun,Xuetao Cao,Chunmei Wang

doi:10.1007/s13238-018-0581-0

Abstract

Polycomb chromobox (CBX) proteins regulate gene transcription by maintaining chromatin states, which guide a variety of biological processes. Now, epigenetic regulation of innate immune response is an emerging field. However, the role of CBX proteins in innate immunity remains unclear. We confirmed that the expression of CBX family proteins, especially Cbx2, was decreased in macrophages upon viral infection, and then we investigated the role of Cbx2 in the antiviral immune response. Silencing or knockdown of Cbx2 in macrophages inhibited virus-induced production of IFN-β. Furthermore, heterozygous Cbx2 knockout were susceptible to VSV challenge. Mechanistically, Cbx2 binds to and recruits Jmjd3 to the Ifnb promoter, leading to demethylation of H3K27me3 and increased transcription of IFN-β. Together, our study reveals a non-traditional function of a Cbx protein and adds new insight into the epigenetic regulation of antiviral innate immunity.

Highlights

The innate immune response is an important determinant in the fight against virus infection, deploying pattern-recognition receptors (PRRs), such as the RIG-I-like receptor (RLR), to Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.sense and respond to pathogens (Cao, 2016; Kawai and Akira, 2010)
Because the expression of Cbx2 is highest in macrophages compared with other immune cells, such as T cells and natural killer cells (Fig. 1B), we focused on investigating the role of Cbx2 in antiviral innate immunity
We identified that Cbx2 enhances virus-induced production of type I interferon, and we defined a molecular mechanism for this regulation in which Cbx2 binds to and recruits Jumonji domain-containing protein D3 (Jmjd3) to the Ifnb promoter, leading to demethylation of H3K27 and promotion of Ifnb transcription

Summary

Introduction

Precise control of the innate immune response is critical for maintaining host immune homeostasis and ensuring proper viral clearance. Epigenetic modifications such as DNA methylation, histone modifications, noncoding RNA regulation and chromatin remodeling have been shown to impact gene transcription. Epigenetic regulation in innate immunity has been studied extensively in recent years, yielding insights into the detailed molecular mechanisms that modulate the expression of inflammatory cytokines and type I interferons (Marcos-Villar et al, 2018; Yoshida et al, 2015; Zhang et al, 2015). Dnmt3a promotes activation of TBK1 by maintaining high expression of the histone deacetylase HDAC9, leading to the production of type I interferons and antiviral innate immunity (Li et al, 2016). The identification of other unknown epigenetic modifier and the underlying mechanisms for innate immunity remain to be further explored

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Conclusion