Bcl6 Sets a Threshold for Antiviral Signaling by Restraining IRF7 Transcriptional Program.

Feng Xu,Hongping Yin,Hang Zhang,Yina Ding,Yanhua Kang,Ningtong Zhuang,Dakang Xu,Liyun Shi,Zhe Lu

doi:10.1038/srep18778

Abstract

The coordination of restraining and priming of antiviral signaling constitute a fundamental aspect of immunological functions. However, we currently know little about the molecular events that can translate the pathogenic cues into the appropriate code for antiviral defense. Our present study reports a specific role of B cell lymphoma (Bcl)6 as a checkpoint in the initiation of the host response to cytosolic RNA viruses. Remarkably, Bcl6 specifically binds to the interferon-regulatory factor (IRF)7 loci and restrains its transcription, thereby functioning as a negative regulator for interferon (IFN)-β production and antiviral responses. The signal-controlled turnover of the Bcl6, most likely mediated by microRNA-127, coordinates the antiviral response and inflammatory sequelae. Accordingly, de-repression of Bcl6 resulted in a phenotypic conversion of macrophages into highly potent IFN-producing cells and rendered mice more resistant to pathogenic RNA virus infection. The failure to remove the Bcl6 regulator, however, impedes the antiviral signaling and exaggerates viral pneumonia in mice. We thus reveal a novel key molecular checkpoint to orchestrate antiviral innate immunity.

Highlights

IRF3 and IRF7 both are master transcription factors required for antiviral immunity
The secretion of IFNβ was significantly decreased in B cell lymphocyte 6 (Bcl6)-deficient cells while increased in Bcl6-expressing cells, inversely correlating with the viral load detected in these cells (Fig. 1f,g)
Based on the above observation, if the B cell lymphoma (Bcl)[6], NcoR2 and HDAC3 ternary complex kept the basal IRF7 transcription in check, how does vesicular stomatitis virus (VSV) stimulation overcome this inhibition to promote antiviral signaling? Interestingly, we reported in a previous study that VSV can trigger a prominent induction of miR-127, a miRNA molecule that has been implicated in Bcl6-mediated cancer development and other pathophysiology[23,31]

Summary

Introduction

IRF3 and IRF7 both are master transcription factors required for antiviral immunity. Compared with IRF3, which is constitutively expressed in the cytosol, IRF7 is likely induced at the transcriptional level following viral exposure. B cell lymphocyte 6 (Bcl6) is a member of the BTB (BR-C, ttk and bab)/POZ (Pox virus and Zinc finger) family and a master transcriptional regulator essential for various physiopathologies[12]. It was originally characterized as an oncogene in diffuse large B cell lymphoma (DLBCL) and was found in some solid tumors, such as bladder, colon cancer and hepatoma[13]. HBV infection can elevate the expression of miR-127, which functioned to fine–tune HBV behavior via modulating endoplasmic reticulum (ER) stress[25] Despite these findings, the exact role of miR-127 in antiviral process and the underlying mechanism are largely undefined. We, for the first time, establish a very specific role of the Bcl[6] in antiviral response and provide a novel mechanism whereby a proto-oncogenic protein instructs host antiviral defense

Methods

Results

Conclusion