Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling

D’Cruz, Akshay A.; Kershaw, Nadia J.; Chiang, Jessica J.; Wang, May K.; Nicola, Nicos A.; Babon, Jeffrey J.; Gack, Michaela U.; Nicholson, Sandra E.

doi:10.1042/bj20121425

Cited by 44 publications

(41 citation statements)

References 63 publications

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“…TRIM25 is widely accepted as a positive regulator of RIG-I signaling, with numerous studies, including our own, describing its regulation of RIG-I response to viral infection and/or its interaction with RIG-I. 14,[31][32][33][34][35][36] The data presented here clearly show that in two human epithelial cell lines and in primary mouse fibroblasts, TRIM25 is not required for a physiological RIG-Imediated immune response to influenza virus infection. The comprehensive nature of our results further indicates that these observations are not simply a consequence of intrinsic differences between mouse and human cells, or differences between cell types.…”

Section: Discussionmentioning

confidence: 72%

“…TRIM25 is widely accepted as a positive regulator of RIG‐I signaling, with numerous studies, including our own, describing its regulation of RIG‐I response to viral infection and/or its interaction with RIG‐I . The data presented here clearly show that in two human epithelial cell lines and in primary mouse fibroblasts, TRIM25 is not required for a physiological RIG‐I‐mediated immune response to influenza virus infection.…”

Section: Discussionmentioning

confidence: 73%

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RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

et al. 2019

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The innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid–inducible gene‐I (RIG‐I) is a pattern recognition receptor that recognizes viral RNA and, when activated, results in the production of type I and III interferons (IFNs) and the upregulation of IFN‐stimulated genes. Ubiquitination of RIG‐I by the E3 ligases tripartite motif‐containing 25 (TRIM25) and Riplet is thought to be requisite for RIG‐I activation; however, recent studies have questioned the relative importance of these two enzymes for RIG‐I signaling. In this study, we show that deletion of Trim25 does not affect the IFN response to either influenza A virus (IAV), influenza B virus, Sendai virus or several RIG‐I agonists. This is in contrast to deletion of either Rig‐i or Riplet, which completely abrogated RIG‐I‐dependent IFN responses. This was consistent in both mouse and human cell lines, as well as in normal human bronchial cells. With most of the current TRIM25 literature based on exogenous expression, these findings provide critical evidence that Riplet, and not TRIM25, is required endogenously for the ubiquitination of RIG‐I. Despite this, loss of TRIM25 results in greater susceptibility to IAV infection in vivo, suggesting that it may have an alternative role in host antiviral defense. This study refines our understanding of RIG‐I signaling in viral infections and will inform future studies in the field.

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Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 73%

RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

et al. 2019

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“…When human TRIM25 RING domain was crystallized with an ubiquitin‐charged E2 conjugating enzyme, UBE2D1, it was shown to form a dimer with both RING monomers contacting the ubiquitin molecule (Koliopoulos, Esposito, Christodoulou, Taylor, & Rittinger, ). Crystal structures have also been generated for the PRY/SPRY domain of mouse TRIM25, showing that its overall structure is that of two anti‐parallel β‐sheets in a sandwich type conformation, similarly to PRY/SPRY domains found in other proteins (D'Cruz et al, ).…”

Section: Trim25's Role In Innate Immunitymentioning

confidence: 90%

TRIM25 and its emerging RNA‐binding roles in antiviral defense

2020

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The innate immune system is the body's first line of defense against viruses, with pattern recognition receptors (PRRs) recognizing molecules unique to viruses and triggering the expression of interferons and other anti-viral cytokines, leading to the formation of an anti-viral state. The tripartite motif containing 25 (TRIM25) is an E3 ubiquitin ligase thought to be a key component in the activation of signaling by the PRR retinoic acid-inducible gene I protein (RIG-I). TRIM25 has recently been identified as an RNA-binding protein, raising the question of whether its RNA-binding activity is important for its role in innate immunity. Here, we review TRIM25's mechanisms and pathways in noninfected and infected cells. We also introduce models that explain how

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“…Where ligand binding to B30.2 domains has been defined by either crystal structures or nonfunctional mutants (34–39, 45), interactions have mapped to the face of the B30.2 domain where these hypervariable loops lie. Although the exact binding sites on this face vary, many involve the central region of the domain (35, 37, 41). In other B30.2 domains where crystal structures are available, this central region has a neutral surface potential (22).…”

Section: Discussionmentioning

confidence: 99%

Sensor Function for Butyrophilin 3A1 in Prenyl Pyrophosphate Stimulation of Human Vγ2Vδ2 T Cells

Wang

Morita

2015

The Journal of Immunology

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Vγ2Vδ2 T cells play important roles in human immunity to pathogens and in cancer immunotherapy by responding to isoprenoid metabolites, such as (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate and isopentenyl pyrophosphate. The Ig superfamily protein butyrophilin (BTN)3A1 was shown to be required for prenyl pyrophosphate stimulation. We proposed that the intracellular B30.2 domain of BTN3A1 binds prenyl pyrophosphates, resulting in a change in the extracellular BTN3A1 dimer that is detected by Vγ2Vδ2 TCRs. Such B30.2 binding was demonstrated recently. However, other investigators reported that the extracellular BTN3A1 IgV domain binds prenyl pyrophosphates, leading to the proposal that the Vγ2Vδ2 TCR recognizes the complex. To distinguish between these mechanisms, we mutagenized residues in the two binding sites and tested the mutant BTN3A1 proteins for their ability to mediate prenyl pyrophosphate stimulation of Vγ2Vδ2 T cells to proliferate and secrete TNF-α. Mutagenesis of residues in the IgV site had no effect on Vγ2Vδ2 T cell proliferation or secretion of TNF-α. In contrast, mutagenesis of residues within the basic pocket and surrounding V regions of the B30.2 domain abrogated prenyl pyrophosphate-induced proliferation. Mutations of residues making hydrogen bonds to the pyrophosphate moiety also abrogated TNF-α secretion, as did mutation of aromatic residues making contact with the alkenyl chain. Some mutations further from the B30.2 binding site also diminished stimulation, suggesting that the B30.2 domain may interact with a second protein. These findings support intracellular sensing of prenyl pyrophosphates by BTN3A1 rather than extracellular presentation.

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Crystal structure of the TRIM25 B30.2 (PRYSPRY) domain: a key component of antiviral signalling

Cited by 44 publications

References 63 publications

RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

RIPLET, and not TRIM25, is required for endogenous RIG‐I‐dependent antiviral responses

TRIM25 and its emerging RNA‐binding roles in antiviral defense

Sensor Function for Butyrophilin 3A1 in Prenyl Pyrophosphate Stimulation of Human Vγ2Vδ2 T Cells

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