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      The ORF3 Protein of Genotype 1 Hepatitis E Virus Suppresses TLR3-induced NF-κB Signaling via TRADD and RIP1

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          Abstract

          Hepatitis E virus (HEV) genotype 1 infection is common and can emerge as outbreaks in developing areas, thus posing a threat to public health. However, due to the absence of feasible animal models, the mechanism of HE pathogenesis remains obscure. The HEV pathogenic mechanism has been suggested to be mediated by the immune system and not by direct viral duplication. We firstly discovered that the open reading frame 3 (ORF3) protein of genotype 1 HEV downregulates TLR3-mediated NF-κB signaling in Human A549 Lung Epithelial Cells (A549 cells) which were exposed to different TLR agonists associated with viral nucleic acids. Additionally, we identified the P2 domain of ORF3 as being responsible for this inhibition. Intriguingly, tumor necrosis factor receptor 1-associated death domain protein (TRADD) expression and receptor-interacting protein kinase 1 (RIP1) K63-ubiquitination were reduced in the presence of both ORF3 and Poly(I:C). Furthermore, we found that Lys377 of RIP1 acts as the functional ubiquitination site for ORF3-associated inhibition. Overall, we found that ORF3 protein downregulates TLR3-mediated NF-κB signaling via TRADD and RIP1. Our findings provide a new perspective on the cellular response in HEV infection and expand our understanding of the molecular mechanisms of HEV pathogenesis in innate immunity.

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          Most cited references30

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          TLR signaling.

          The TLR family senses the molecular signatures of microbial pathogens, and plays a fundamental role in innate immune responses. TLRs signal via a common pathway that leads to the expression of diverse inflammatory genes. In addition, each TLR elicits specific cellular responses to pathogens owing to differential usage of intracellular adapter proteins. Recent studies have revealed the importance of the subcellular localization of TLRs in pathogen recognition and signaling. TLR signaling pathways is negatively regulated by a number of cellular proteins to attenuate inflammation. Here, we describe recent advances in our understanding of the regulation of TLR-mediated signaling.
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            Toll-like receptor and RIG-I-like receptor signaling.

            Toll-like receptors (TLRs) and RIG-I-like receptors (RLRs) constitute distinct families of pattern-recognition receptors that sense nucleic acids derived from viruses and trigger antiviral innate immune responses. TLR3, TLR7, and TLR9 are membrane proteins localized to the endosome that recognize viral double-stranded RNA, single-stranded RNA, and DNA, respectively, while RLRs, including RIG-I, Mda5, and LGP2, are cytoplasmic proteins that recognize viral RNA. Upon recognition of these nucleic acid species, TLRs and RLRs recruit specific intracellular adaptor proteins to initiate signaling pathways culminating in activation of NF-kappaB, MAP kinases, and IRFs that control the transcription of genes encoding type I interferon and other inflammatory cytokines, which are important for eliminating viruses. Here, we review recent insights into the signaling pathways initiated by TLR and RLR and their roles in innate and adaptive immune responses.
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              Ubiquitylation in innate and adaptive immunity.

              Protein ubiquitylation has emerged as a key mechanism that regulates immune responses. Much like phosphorylation, ubiquitylation is a reversible covalent modification that regulates the stability, activity and localization of target proteins. As such, ubiquitylation regulates the development of the immune system and many phases of the immune response, including its initiation, propagation and termination. Recent work has shown that several ubiquitin ligases help to prevent the immune system from attacking self tissues. The dysfunction of several ubiquitin ligases has been linked to autoimmune diseases.
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                Author and article information

                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group
                2045-2322
                08 June 2016
                2016
                : 6
                : 27597
                Affiliations
                [1 ]Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, 430030, China
                [2 ]National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Public Health, Xiamen University , Xiamen, 361005, China
                [3 ]Department of Infectious Disease, the Central Hospital of Fuling District , Chongqing, 404100, China
                Author notes
                Article
                srep27597
                10.1038/srep27597
                4897786
                27270888
                a160f99c-f6e0-4ff8-8a1b-9a87a64e0f38
                Copyright © 2016, Macmillan Publishers Limited

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 22 March 2016
                : 23 May 2016
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