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      Regulation of TRIF-mediated innate immune response by K27-linked polyubiquitination and deubiquitination

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          Abstract

          TIR domain-containing adaptor inducing interferon-β (TRIF) is an essential adaptor protein required for innate immune responses mediated by Toll-like receptor (TLR) 3- and TLR4. Here we identify USP19 as a negative regulator of TLR3/4-mediated signaling. USP19 deficiency increases the production of type I interferons (IFN) and proinflammatory cytokines induced by poly(I:C) or LPS in vitro and in vivo. Usp19 -/- mice have more serious inflammation after poly(I:C) or LPS treatment, and are more susceptible to inflammatory damages and death following Salmonella typhimurium infection. Mechanistically, USP19 interacts with TRIF and catalyzes the removal of TRIF K27-linked polyubiquitin moieties, thereby impairing the recruitment of TRIF to TLR3/4. In addition, the RING E3 ubiquitin ligase complex Cullin-3-Rbx1-KCTD10 catalyzes K27-linked polyubiquitination of TRIF at K523, and deficiency of this complex inhibits TLR3/4-mediated innate immune signaling. Our findings thus reveal TRIF K27-linked polyubiquitination and deubiquitination as a critical regulatory mechanism of TLR3/4-mediated innate immune responses.

          Abstract

          TRIF is an important adaptor protein for mediating Toll-like receptor (TLR) 3 and TLR4 signaling. Here the authors show that the deubiquitinating enzymes USP19, as well as the E3 ubiquitin ligase complex Cullin-3-Rbx1-KCTD10, modulates TRIF K523 ubiquitination and thereby TRIF recruitment to TLR3/4 to control innate immunity.

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          Most cited references30

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          Toll-like receptors: critical proteins linking innate and acquired immunity.

          Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.
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            IRFs: master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors.

            The interferon-regulatory factor (IRF) family of transcription factors was initially found to be involved in the induction of genes that encode type I interferons. IRFs have now been shown to have functionally diverse roles in the regulation of the immune system. Recently, the crucial involvement of IRFs in innate and adaptive immune responses has been gaining much attention, particularly with the discovery of their role in immunoregulation by Toll-like receptors and other pattern-recognition receptors.
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              Unresponsiveness of MyD88-deficient mice to endotoxin.

              MyD88 is a general adaptor protein that plays an important role in the Toll/IL-1 receptor family signalings. Recently, Toll-like receptors 2 and 4 (TLR2 and TLR4) have been suggested to be the signaling receptors for lipopolysaccharide (LPS). In this study, we demonstrate that MyD88 knockout mice lack the ability to respond to LPS as measured by shock response, B cell proliferative response, and secretion of cytokines by macrophages and embryonic fibroblasts. However, activation of neither NF-kappaB nor the mitogen-activated protein (MAP) kinase family is abolished in MyD88 knockout mice. These findings demonstrate that signaling via MyD88 is essential for LPS response, but the inability of MyD88 knockout mice to induce LPS-dependent gene expression cannot simply be attributed to lack of the activation of MAP kinases and NF-kappaB.
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                Author and article information

                Contributors
                shuh@whu.edu.cn
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                11 September 2019
                11 September 2019
                2019
                : 10
                Affiliations
                [1 ]Department of Infectious Diseases, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, 430071 Wuhan, China
                [2 ]ISNI 0000 0001 2331 6153, GRID grid.49470.3e, Department of Cell Biology, College of Life Sciences, , Wuhan University, ; 430072 Wuhan, China
                Article
                12145
                10.1038/s41467-019-12145-1
                6739404
                31511519
                f403e538-99b8-4a64-8c88-b1648d3d7b2c
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 31870870
                Award ID: 31830024
                Award Recipient :
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                © The Author(s) 2019

                Uncategorized
                ubiquitylation,bacterial infection,innate immune cells,pattern recognition receptors

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