P200 family protein IFI204 negatively regulates type I interferon responses by targeting IRF7 in nucleus.

Liu Cao,Yongjia Tong,Qianyun Liu,Zhen Zhang,Xiaolu Zhao,Deyin Guo,Xiaolong Guo,Yu Chen,Chun-Mei Li,Lanyi Zeng,Shuting Guo,Yanxi Ji,Pinghui Feng

doi:10.1371/journal.ppat.1008079

Liu Cao, Yongjia Tong + Show 11 more

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https://doi.org/10.1371/journal.ppat.1008079

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Journal: PLoS pathogens	Publication Date: Oct 11, 2019
Citations: 60	License type: CC BY 4.0

Affiliation: Wuhan University, Sun Yat-sen University

Abstract

Interferon-inducible p200 family protein IFI204 was reported to be involved in DNA sensing, and subsequently induces the production of type I interferons and proinflammatory mediators. However, its function in the regulation of antiviral innate immune signaling pathway remains unclear. Here we reported a novel role of IFI204 that specifically inhibits the IRF7-mediated type I interferons response during viral infection. IFI204 and other p200 family proteins are highly expressed in mouse hepatitis coronavirus-infected bone marrow-derived dendritic cells. The abundant IFI204 could significantly interact with IRF7 in nucleus by its HIN domain and prevent the binding of IRF7 with its corresponding promoter. Moreover, other p200 family proteins that possess HIN domain could also inhibit the IRF7-mediated type I interferons. These results reveal that, besides the positive regulation function in type I interferon response at the early stage of DNA virus infection, the interferon-inducible p200 family proteins such as IFI204 could also negatively regulate the IRF7-mediated type I interferon response after RNA virus infection to avoid unnecessary host damage from hyper-inflammatory responses.

Highlights

The interferon (IFN)-mediated innate immune response is important for the control of viral infection by the effect of downstream IFN-stimulated genes (ISGs) [1]
We demonstrate that IFI204 can inhibit IRF7-mediated activation of type I IFN responses induced by RNA virus infection, which is in contrast with its role in IRF3 activation in cyclic GMP-AMP synthase (cGAS)
TLR3 recognizes dsRNA and recruits the adaptor molecule TRIF to promote IRF3/7 import into the nucleus to activate the expression of type I IFNs and ISGs [14, 15]; TLR7/8 detect ssRNA and recruit the adaptor molecule myeloid differentiation primaryresponse protein 88 (MyD88) to activate IRF7 to trigger the expression of type I IFNs [16, 17]

Summary

Introduction

The interferon (IFN)-mediated innate immune response is important for the control of viral infection by the effect of downstream IFN-stimulated genes (ISGs) [1]. TLR3 recognizes dsRNA and recruits the adaptor molecule TRIF to promote IRF3/7 import into the nucleus to activate the expression of type I IFNs and ISGs [14, 15]; TLR7/8 detect ssRNA and recruit the adaptor molecule myeloid differentiation primaryresponse protein 88 (MyD88) to activate IRF7 to trigger the expression of type I IFNs [16, 17] Both of the cytoplasmic DNA sensor cGAS and ALRs, including AIM2, IFI16 and IFI204, can activate the STING-IRF3 signaling pathway to induce the type I IFNs [4, 18,19,20,21]

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