Cell type-specific function of TRAF2 and TRAF3 in regulating type I IFN induction

Xiaoping Xie,Yanchuan Li,Shao-Cong Sun,Zuliang Jie,Pingwei Li,Jin Jin,Baoyu Zhao,Lele Zhu,Xuhong Cheng

doi:10.1186/s13578-018-0268-5

Abstract

BackgroundTRAF3 is known as a central mediator of type I interferon (IFN) induction by various pattern recognition receptors, but the in vivo function of TRAF3 in host defense against viral infection is poorly defined due to the lack of a viable mouse model.ResultsHere we show that mice carrying conditional deletion of TRAF3 in myeloid cells or dendritic cells do not have a significant defect in host defense against vesicular stomatitis virus (VSV) infection. However, whole-body inducible deletion of TRAF3 renders mice more sensitive to VSV infection. Consistently, TRAF3 was essential for type I IFN induction in mouse embryonic fibroblasts (MEFs) but not in macrophages. In dendritic cells, TRAF3 was required for type I IFN induction by TLR ligands but not by viruses. We further show that the IFN-regulating function is not unique to TRAF3, since TRAF2 is an essential mediator of type I IFN induction in several cell types, including macrophages, DCs, and MEFs.ConclusionsThese findings suggest that both TRAF2 and TRAF3 play a crucial role in type I IFN induction, but their functions are cell type- and stimulus-specific.

Highlights

TRAF3 is known as a central mediator of type I interferon (IFN) induction by various pattern recognition receptors, but the in vivo function of TRAF3 in host defense against viral infection is poorly defined due to the lack of a viable mouse model
Induction of type I IFNs is typically mediated by pattern-recognition receptors (PRRs), including toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors, and the cytosolic GAMP synthase, which detect various molecular patterns associated with viral genomes or replication products [2, 3]
In vivo function of TRAF3 in host defense against viral infection Germline deletion of TRAF3 causes postnatal lethality, which has hampered studies to examine in vivo functions of TRAF3 [12]

Summary

Introduction

TRAF3 is known as a central mediator of type I interferon (IFN) induction by various pattern recognition receptors, but the in vivo function of TRAF3 in host defense against viral infection is poorly defined due to the lack of a viable mouse model. Induction of type I IFNs is typically mediated by pattern-recognition receptors (PRRs), including toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors, and the cytosolic GAMP synthase (cGAS), which detect various molecular patterns associated with viral genomes or replication products [2, 3]. Mitochondrial antiviral-signaling protein (MAVS, known as VISA and IPS-1) serves as an adaptor of RLRs, whereas stimulator of interferon gene (STING) mediates type I IFN induction by cGAS and other cytoplasmic DNA sensors [2, 4]. Phosphorylated IRF3 forms a dimer and translocates to the nucleus to participate in the induction of type I IFN genes

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Conclusion