Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition

Koliopoulos, Marios G.; Lethier, Mathilde; Veen, Annemarthe G. van der; Haubrich, Kevin; Hennig, Janosch; Kowalinski, Eva; Stevens, Rebecca V.; Martin, Stephen R.; Sousa, Caetano Reis e; Cusack, Stephen; Rittinger, Katrin

doi:10.1038/s41467-018-04214-8

Cited by 139 publications

(230 citation statements)

References 70 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: 73%

“…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%

“…TRIM25 is one of the multiple host proteins targeted by the influenza virus nonstructural protein 1, which binds to the CC region of TRIM25 and is thought to act by altering the relative positioning of the TRIM25-PRYSPRY domain. 36 Several groups have suggested that TRIM25 can directly bind to viral RNA and propose that its antiviral functions are conferred by formation of ribonucleoprotein complexes that effectively hinder viral replication. 20,29 In these studies, RIG-I independence was evidenced by the effect of compound deletion of Rig-i and Trim25 in A549 cells and a corresponding increase in levels of IAV H3N2 A/ Udorn virus.…”

Section: Discussionmentioning

confidence: 99%

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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: 73%

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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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 KAP1 RBCC motif has been reported to form homotrimers and bind KRAB domains with a stoichiometry of 3:1 KAP1:KRAB (21,22). However, this is inconsistent with more recent reports that TRIM5, TRIM25 and TRIM69 form antiparallel dimers, a property predicted to be conserved across the TRIM family (23)(24)(25)(26). Moreover, various TRIMs (TRIM5, PML/TRIM19, TRIM32) further 90 assemble into tetramers and higher-order oligomers, including two-dimensional lattices and molecular scaffolds (as seen in PML bodies), and these higher-order assemblies are important for their biological activities (25,(27)(28)(29).…”

Section: Introductionmentioning

confidence: 82%

“…Each of the domains within the RBCC motif (RING, B-box 1, B-box 2 and coiled coil) has been reported to independently form dimers or oligomers in TRIM-family proteins (23)(24)(25)(26)(27)(28)(29). The presence of two or more domains capable of oligomerization independently can lead to polymerization of TRIMs into lattices or scaffolds (25,27,28), but it remains unclear whether this 110 applies to KAP1.…”

Section: Kap1 Forms Dimers That Self-assemble Into Higher-order Oligomentioning

confidence: 99%

Structure of the tripartite motif of KAP1/TRIM28 identifies molecular interfaces required for transcriptional silencing of retrotransposons

Stoll

Oda

Chong

et al. 2018

Preprint

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Transcription of transposable elements is tightly regulated to prevent genome damage. KRAB domain-containing zinc finger proteins (KRAB-ZFPs) and KRAB-associated protein 1 (KAP1/TRIM28) play a key role in regulating retrotransposons. KRAB-ZFPs recognize specific 15 retrotransposon sequences and recruit KAP1, inducing the assembly of an epigenetic silencing complex, with chromatin remodeling activities that repress transcription of the targeted retrotransposon and adjacent genes. Our biophysical and structural data show that the tripartite motif (TRIM) of KAP1 forms antiparallel dimers, which further assemble into tetramers and higherorder oligomers in a concentration-dependent manner. Structure-based mutations in the B-box 1 20 domain prevent higher-order oligomerization without significant loss of retrotransposon silencing activity, indicating that, in contrast to other TRIM-family proteins, self-assembly is not essential for KAP1 function. The crystal structure of the KAP1 TRIM dimer identifies the KRAB domain binding site, in the coiled-coil domain near the dyad. Mutations at this site abolished KRAB binding and transcriptional silencing activity of KAP1. This work identifies the interaction interfaces in the 25 KAP1 TRIM responsible for self-association and KRAB binding and establishes their role in retrotransposon silencing. Keywords Transcriptional repressor; epigenetic silencing; endogenous retrovirus; transposable element; ubiquitin E3 ligase 30 2 Running title Structure and function of KAP1/TRIM28 Significance Retroviruses can integrate their DNA into the host-cell genome. Inherited retroviral DNA and other transposable elements account for over half of the human genome. Transposable elements must be tightly regulated to restrict their proliferation and prevent toxic gene expression. KAP1/TRIM2835 is an essential regulator of transposable element transcription. We determined the crystal structure of the KAP1 TRIM. The structure identifies a protein-protein interaction site required for recruitment of KAP1 to transposable elements. An epigenetic gene silencing assay confirms the importance of this site for KAP1-dependent silencing. We also show that KAP1 self-assembles in solution, but this self-assembly is not required for silencing. Our work provides insights into KAP1-40 dependent silencing, and tools for expanding our mechanistic understanding of this process. /body

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Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class

et al. 2021

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The ubiquitylation machinery regulates several fundamental biological processes from protein homeostasis to a wide variety of cellular signaling pathways. As a consequence, its dysregulation is linked to diseases including cancer, neurodegeneration, and autoimmunity. With this review, we aim to highlight the therapeutic potential of targeting E3 ligases, with a special focus on an emerging class of RING ligases, named tri‐partite motif (TRIM) proteins, whose role as targets for drug development is currently gaining pharmaceutical attention. TRIM proteins exert their catalytic activity as scaffolds involved in many protein–protein interactions, whose multidomains and adapter‐like nature make their druggability very challenging. Herein, we give an overview of the current understanding of this class of single polypeptide RING E3 ligases and discuss potential targeting options.

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Molecular mechanism of influenza A NS1-mediated TRIM25 recognition and inhibition

Cited by 139 publications

References 70 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

Structure of the tripartite motif of KAP1/TRIM28 identifies molecular interfaces required for transcriptional silencing of retrotransposons

Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class

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