title: Soluble IL-6 Receptor and IL-27 Subunit p28 Protein Complex Mediate the Antiviral Response through the Type III IFN Pathway.
abstract: Previously, we demonstrated that the soluble IL-6R (sIL-6R) plays an important role in the host antiviral response through induction of type I IFN and sIL-6R-mediated antiviral action via the IL-27 subunit p28; however, the mechanism that underlies sIL-6R and p28 antiviral action and whether type III IFN is involved remain unknown. In this study, we constructed a sIL-6R and p28 fusion protein (sIL-6R/p28 FP) and demonstrated that the fusion protein has stronger antiviral activity than sIL-6R alone. Consequently, knockout of sIL-6R inhibited virus-triggered IFN-λ1 expression. In addition, sIL-6R/p28 FP associated with mitochondrial antiviral signaling protein and TNFR-associated factor 6, the retinoic acid-inducible gene I adapter complex, and the antiviral activity mediated by sIL-6R/p28 FP was dependent on mitochondrial antiviral signaling protein. Furthermore, significantly reduced binding of p50/p65 and IFN regulatory factor 3 to the IFN-λ1 promoter was observed in sIL-6R knockout cells compared with the control cells. Interestingly, a novel heterodimer of c-Fos and activating transcription factor 1 was identified as a crucial transcriptional activator of IFN-λ1 The sIL-6R/p28 FP upregulated IFN-λ1 expression by increasing the binding abilities of c-Fos and activating transcription factor 1 to the IFN-λ1 promoter via the p38 MAPK signaling pathway. In conclusion, these results demonstrate the important role of sIL-6R/p28 FP in mediating virus-induced type III IFN production.
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Zhangchuan
authors.initials: Z
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Zhongying
authors.initials: Z
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Shi
authors.initials: S
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan 430072, China yingzhu@whu.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D051697:Activating Transcription Factor 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism; D007372:Interferons / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D064094:Interleukin-27 / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D021122:Protein Subunits / Q000276:immunology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000172:deficiency / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D051697:Activating Transcription Factor 1; C508600:IL6 protein, human; D050838:Interferon Regulatory Factor-3; D064094:Interleukin-27; D015850:Interleukin-6; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D007372:Interferons; D048051:p38 Mitogen-Activated Protein Kinases