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      TRIM Proteins and Their Roles in Antiviral Host Defenses

      1 , 1 , 1
      Annual Review of Virology
      Annual Reviews

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          Abstract

          Tripartite motif (TRIM) proteins are a versatile family of ubiquitin E3 ligases involved in a multitude of cellular processes. Studies in recent years have demonstrated that many TRIM proteins play central roles in the host defense against viral infection. While some TRIM proteins directly antagonize distinct steps in the viral life cycle, others regulate signal transduction pathways induced by innate immune sensors, thereby modulating antiviral cytokine responses. Furthermore, TRIM proteins have been implicated in virus-induced autophagy and autophagy-mediated viral clearance. Given the important role of TRIM proteins in antiviral restriction, it is not surprising that several viruses have evolved effective maneuvers to neutralize the antiviral action of specific TRIM proteins. Here, we describe the major antiviral mechanisms of TRIM proteins as well as viral strategies to escape TRIM-mediated host immunity.

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          Most cited references117

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          Influenza A virus NS1 targets the ubiquitin ligase TRIM25 to evade recognition by the host viral RNA sensor RIG-I.

          The ubiquitin ligase TRIM25 mediates Lysine 63-linked ubiquitination of the N-terminal CARD domains of the viral RNA sensor RIG-I to facilitate type I interferon (IFN) production and antiviral immunity. Here, we report that the influenza A virus nonstructural protein 1 (NS1) specifically inhibits TRIM25-mediated RIG-I CARD ubiquitination, thereby suppressing RIG-I signal transduction. A novel domain in NS1 comprising E96/E97 residues mediates its interaction with the coiled-coil domain of TRIM25, thus blocking TRIM25 multimerization and RIG-I CARD domain ubiquitination. Furthermore, a recombinant influenza A virus expressing an E96A/E97A NS1 mutant is defective in blocking TRIM25-mediated antiviral IFN response and loses virulence in mice. Our findings reveal a mechanism by which influenza virus inhibits host IFN response and also emphasize the vital role of TRIM25 in modulating antiviral defenses.
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            Assembly and localization of Toll-like receptor signalling complexes.

            Signal transduction by the Toll-like receptors (TLRs) is central to host defence against many pathogenic microorganisms and also underlies a large burden of human disease. Thus, the mechanisms and regulation of signalling by TLRs are of considerable interest. In this Review, we discuss the molecular basis for the recognition of pathogen-associated molecular patterns, the nature of the protein complexes that mediate signalling, and the way in which signals are regulated and integrated at the level of allosteric assembly, post-translational modification and subcellular trafficking of the components of the signalling complexes. These fundamental molecular mechanisms determine whether the signalling output leads to a protective immune response or to serious pathologies such as sepsis. A detailed understanding of these processes at the molecular level provides a rational framework for the development of new drugs that can specifically target pathological rather than protective signalling in inflammatory and autoimmune disease.
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              Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity.

              RIG-I detects invading viral RNA and activates the transcription factors NF-kappaB and IRF3 through the mitochondrial protein MAVS. Here we show that RNA bearing 5'-triphosphate strongly activates the RIG-I-IRF3 signaling cascade in a reconstituted system composed of RIG-I, mitochondria, and cytosol. Activation of RIG-I requires not only RNA but also polyubiquitin chains linked through lysine 63 (K63) of ubiquitin. RIG-I binds specifically to K63-polyubiquitin chains through its tandem CARD domains in a manner that depends on RNA and ATP. Mutations in the CARD domains that abrogate ubiquitin binding also impair RIG-I activation. Remarkably, unanchored K63-ubiquitin chains, which are not conjugated to any target protein, potently activate RIG-I. These ubiquitin chains function as an endogenous ligand of RIG-I in human cells. Our results delineate the mechanism of RIG-I activation, identify CARD domains as a ubiquitin sensor, and demonstrate that unanchored K63-polyubiquitin chains are signaling molecules in antiviral innate immunity. Copyright 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Annual Review of Virology
                Annu. Rev. Virol.
                Annual Reviews
                2327-056X
                2327-0578
                September 29 2018
                September 29 2018
                : 5
                : 1
                : 385-405
                Affiliations
                [1 ]Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, USA;, ,
                Article
                10.1146/annurev-virology-092917-043323
                6186430
                29949725
                6c585dc1-33ea-4855-9ef0-45e0edfb2543
                © 2018
                History

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