Mechanism of TRIM25 Catalytic Activation in the Antiviral RIG-I Pathway

Sanchez, Jacint G.; Chiang, Jessica J.; Sparrer, Konstantin M. J.; Alam, Steven L.; Chi, Michael; Roganowicz, Marcin D.; Sankaran, Banumathi; Gack, Michaela U.; Pornillos, Owen

doi:10.1016/j.celrep.2016.06.070

Cited by 121 publications

(181 citation statements)

References 53 publications

(112 reference statements)

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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 . 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%

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%

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

et al. 2019

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“…Two subunits pack in an anti‐parallel manner, forming an elongated rod‐shaped scaffold with a RING domain on each end; the two RING domains are separated by 17–20 nm and so cannot directly interact with each other. On the other hand, other studies have shown that the isolated RING domains of TRIM5α, TRIM25, and TRIM32 engage E2–Ub conjugates and catalyze Ub conjugation as close‐packed dimers . Taken together, these observations imply that the catalytically active form of TRIMs comprises at least two coiled‐coil mediated dimers (four protein molecules).…”

Section: Introductionmentioning

confidence: 84%

Structure and catalytic activation of the TRIM23 RING E3 ubiquitin ligase

et al. 2017

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Tripartite motif (TRIM) proteins comprise a large family of RING-type ubiquitin E3 ligases that regulate important biological processes. An emerging general model is that TRIMs form elongated antiparallel coiled-coil dimers that prevent interaction of the two attendant RING domains. The RING domains themselves bind E2 conjugating enzymes as dimers, implying that an active TRIM ligase requires higher-order oligomerization of the basal coiled-coil dimers. Here, we report crystal structures of the TRIM23 RING domain in isolation and in complex with an E2-ubiquitin conjugate. Our results indicate that TRIM23 enzymatic activity requires RING dimerization, consistent with the general model of TRIM activation.

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“…4A). Bacterially expressed Flag-tagged NZAP protein was incubated with purified proteins that are required for ubiquitination, including ubiquitin, Uba1 (E1), an E2 complex for TRIM25 Uev1a-Ubc13 (38,39), and TRIM25. The resulting NZAP proteins were detected by Western blotting with an anti-Flag antibody.…”

Section: Resultsmentioning

confidence: 99%

TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein

Zheng

Wang

et al. 2017

J Virol

130

168

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Zinc finger antiviral protein (ZAP) is a host factor that specifically inhibits the replication of certain viruses by binding to viral mRNAs and repressing the translation and/or promoting the degradation of target mRNA. In addition, ZAP regulates the expression of certain cellular genes. Here, we report that tripartite motif-containing protein 25 (TRIM25), a ubiquitin E3 ligase, is required for the antiviral activity of ZAP. Downregulation of endogenous TRIM25 abolished ZAP's antiviral activity. The E3 ligase activity of TRIM25 is required for this regulation. TRIM25 mediated ZAP ubiquitination, but the ubiquitination of ZAP itself did not seem to be required for its antiviral activity. Downregulation of endogenous ubiquitin or overexpression of the deubiquitinase OTUB1 impaired ZAP's activity. We provide evidence indicating that TRIM25 modulates the target RNA binding activity of ZAP. These results uncover a mechanism by which the antiviral activity of ZAP is regulated.IMPORTANCE ZAP is a host antiviral factor that specifically inhibits the replication of certain viruses, including HIV-1, Sindbis virus, and Ebola virus. ZAP binds directly to target mRNA, and it represses the translation and promotes the degradation of target mRNA. While the mechanisms by which ZAP posttranscriptionally inhibits target RNA expression have been extensively studied, how its antiviral activity is regulated is not very clear. Here, we report that TRIM25, a ubiquitin E3 ligase, is required for the antiviral activity of ZAP. Downregulation of endogenous TRIM25 remarkably abolished ZAP's activity. TRIM25 is required for ZAP optimal binding to target mRNA. These results help us to better understand how the antiviral activity of ZAP is regulated.

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Mechanism of TRIM25 Catalytic Activation in the Antiviral RIG-I Pathway

Cited by 121 publications

References 53 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 and catalytic activation of the TRIM23 RING E3 ubiquitin ligase

TRIM25 Is Required for the Antiviral Activity of Zinc Finger Antiviral Protein

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