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Cell Type-Specific Function of TRAF2 and TRAF3 in Regulating Type I IFN

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Cell Type-Specific Function of TRAF2 and TRAF3 in Regulating Type I IFN Xie et al. Cell Biosci (2019) 9:5 https://doi.org/10.1186/s13578-018-0268-5 Cell & Bioscience RESEARCH Open Access Cell type‑specifc function of TRAF2 and TRAF3 in regulating type I IFN induction Xiaoping Xie1, Jin Jin2, Lele Zhu1, Zuliang Jie1, Yanchuan Li1, Baoyu Zhao3, Xuhong Cheng1, Pingwei Li3 and Shao‑Cong Sun1,4* Abstract Background: 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 defned due to the lack of a viable mouse model. Results: Here we show that mice carrying conditional deletion of TRAF3 in myeloid cells or dendritic cells do not have a signifcant 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 fbroblasts (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 mac‑ rophages, DCs, and MEFs. Conclusions: These fndings suggest that both TRAF2 and TRAF3 play a crucial role in type I IFN induction, but their functions are cell type- and stimulus-specifc. Keywords: TRAF2, TRAF3, Type I interferon, Antiviral immunity Background IPS-1) serves as an adaptor of RLRs, whereas stimulator Type I interferon (IFN) plays a crucial role in innate of interferon gene (STING) mediates type I IFN induc- immunity against viral infections [1, 2]. Induction of tion by cGAS and other cytoplasmic DNA sensors [2, type I IFNs is typically mediated by pattern-recognition 4]. A common downstream target of the diferent PRR receptors (PRRs), including toll-like receptors (TLRs), pathways is the protein kinase TBK1, which upon activa- RIG-I-like receptors (RLRs), NOD-like receptors, and the tion phosphorylates and activates the transcription factor cytosolic GAMP synthase (cGAS), which detect various interferon regulatory factor 3 (IRF3) [4, 5]. Phosphoryl- molecular patterns associated with viral genomes or rep- ated IRF3 forms a dimer and translocates to the nucleus lication products [2, 3]. In response to ligand stimulation, to participate in the induction of type I IFN genes. the PRRs transduce signals via specifc signaling adaptors. Activation of TBK1 and IRF3 by the PRRs also TIR-domain-containing adapter-inducing interferon-β requires members of the tumor necrosis factor recep- (TRIF) mediates type I IFN induction by TLR3 and TLR4 tor (TNFR)-associated factors (TRAFs) family [3, 6]. upon stimulation by double-stranded RNA and lipopol- TRAFs are adaptor proteins or E3 ubiquitin ligases ysaccharide (LPS), respectively. Mitochondrial antivi- that transduce signals from TNFR superfamily as well ral-signaling protein (MAVS, also known as VISA and as other immune receptors, including the PRRs [7]. While the typical functions of TRAFs include activa- tion of NF-kB and MAP kinase signaling pathways, *Correspondence: [email protected] TRAF3 has been shown to mediate activation of IRF3 1 Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX 77030, USA and implicated as a common signaling adaptor for type Full list of author information is available at the end of the article I IFN induction [2, 8, 9]. However, whether TRAF3 is a © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Xie et al. Cell Biosci (2019) 9:5 Page 2 of 10 specifc TRAF member that mediates type I IFN induc- type I IFN induction. Te results provide new insight into tion is in debate, since in some systems other TRAF the physiological function of TRAF proteins in mediating members are also involved in the type I IFN induction antiviral innate immunity. [10, 11]. Te in vivo function of TRAF3 in mediating antiviral host defense is also poorly defned, since cur- Results rent studies have been largely relied on in vitro sys- In vivo function of TRAF3 in host defense against viral tems using immortalized mouse embryonic fbroblasts infection (MEFs) or other cell lines. Germline deletion of TRAF3 causes postnatal lethality, To study the physiological function of TRAF3 in anti- which has hampered studies to examine in vivo func- viral innate immunity, we employed TRAF3 conditional tions of TRAF3 [12]. To study the in vivo role of TRAF3 knockout (KO) mice carrying TRAF3 defciencies in dif- in regulating antiviral innate immunity, we generated ferent immune cell types or with inducible deletion of myeloid cell-conditional Traf3 KO (Traf3f/fLyz2-Cre; TRAF3 in adult mice. We obtained genetic evidence that hereafter called Traf3MKO) mice by crossing Traf3-fox whole-body inducible deletion of TRAF3 in adult mice mice [13] with Lyz2-Cre [14]. We then challenged these attenuated their host defense against vesicular stomati- mice with VSV, a frequently used model for studying tis virus (VSV) infection. Surprisingly, however, TRAF3 host defense against RNA virus infections [15]. VSV was dispensable in both myeloid cells and dendritic cells is known to induce type I IFN induction via the cyto- for this innate immune function. Using primary cells, plasmic RNA-responsive PRR RIG-I [15]. Surprisingly, we further demonstrated that the function of TRAF3 in TRAF3 deletion in myeloid cells did not sensitize mice to mediating type I IFN induction is cell type- and stimulus- VSV infection, since the Traf3MKO and wild-type control specifc. Moreover, this innate immune function is not mice displayed comparable survival rate following intra- unique for TRAF3, since TRAF2 is equally important for venous (i.v.) infection with VSV (Fig. 1a). Since dendritic a b 100 P=0.5377 100 ) n=8 ) n=8 80 80 (% (% 60 60 40 40 P=0.3362 Survival 20 WT Survival 20 WT Traf3MKO Traf3DC-KO 0 0 024 6 8 10 12 14 024 6 8 10 12 14 Days post infection Days post infection c Spleno- d cytes 100 LN cells ) n=15 80 P=0.035 WT IKO WT IKO (% 60 TRAF3 40 Survival 20 WT Tubulin Traf3IKO 0 024 6 8 10 12 14 Days post infection Fig. 1 Survival of Traf3 conditional KO mice following VSV infection. a Age‑matched (6–8 weeks old) WT and Traf3MKO mice were infected i.v. with VSV (1 107 PFU per mouse). Data are presented as 8 animals/group. b Traf3DC‑KO and WT littermate control mice were infected i.v. with × VSV (2 107 PFU per mouse). Survival was recorded and presented as 8 mice per group. c Immunoblot analysis of the indicated proteins in the × extracts of splenocytes or LN cells derived from Tamoxifen‑treated WT and TRAF3IKO mice. d WT and TRAF3IKO mice (n 15) were infected with VSV = (2 107 PFU per mouse) via tail vein. Data representative of two independent experiments, and statistical signifcance was determined by log‑rank × and Gehan‑Wilcoxon tests. p < 0.05 indicates signifcantly diferent Xie et al. Cell Biosci (2019) 9:5 Page 3 of 10 cells (DCs) also play a crucial role in regulating antiviral (Fig. 2f), ISD (Fig. 2g) or DMXAA (Fig. 2h). Consist- immunity, we next examined the in vivo role of TRAF3 ently, while TRAF3 defciency promoted the activation in DCs by generating DC-conditional Traf3 KO (Traf3f/ of STING/TBK1/IRF3 signaling pathways by HSV-1 fCd11c-Cre; here after called Traf3DC-KO) mice. Simi- (Fig. 2i), it attenuated these signaling events induced by lar to the Traf3MKO mice, the Traf3DC-KO mice did not cGAMP (Fig. 2j). Tese results suggest that TRAF3 may show enhanced sensitivity to VSV infection compared play diferent roles in regulating STING activation and to their age-matched wild-type control mice (Fig. 1b). upstream signaling steps in the DNA-sensing pathway. Tese results suggest that TRAF3 is dispensable in innate To examine the role of TRAF3 in innate immune cells, immune cells for host defense against VSV infections. we prepared primary bone barrow derived macrophages To further investigate the antiviral innate immune (BMDMs) from Traf3MKO and wild-type control mice. In function of TRAF3, we employed an inducible KO sys- contrast to the results obtained with MEFs, TRAF3 dele- tem allowing TRAF3 deletion in diferent cell types in tion in BMDMs had no efect on the induction of Ifna and adult mice. We crossed the Traf3-fox mice with trans- Ifnb genes by VSV or SeV (Fig. 2k, l). On the other hand, genic mice expressing a tamoxifen-inducible Cre recom- as seen in MEFs, the TRAF3 defciency in macrophages binase, ER-Cre [16]. We then injected the Traf3f/fERCre/+ promoted type I IFN induction by the DNA virus HSV and control Traf3f/f mice with tamoxifen to generate (Fig. 2m). Furthermore, TRAF3 was completely dispensa- the Traf3 inducible KO (Traf3IKO) and wild-type con- ble for the induction of Ifna and Ifnb by the TLR ligands trol mice. Immunoblot analysis using splenocytes and LPS and polyI:C (Fig. 2n, o). Consistently, loss of TRAF3 lymph node cells revealed efcient deletion of TRAF3 in in macrophages did not afect LPS-stimulated phospho- the Traf3IKO mice (Fig.
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