Interferon-stimulated TRIM69 interrupts dengue virus replication by ubiquitinating viral nonstructural protein 3

Wang, Kezhen; Zou, Chunling; Wang, Xiujuan; Huang, Chenxiao; Feng, Tingting; Pan, Wen; Wu, Qihan; Wang, Penghua; Dai, Jianfeng

doi:10.1371/journal.ppat.1007287

Cited by 77 publications

(79 citation statements)

References 68 publications

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“…Although proteasome-mediated degradation of NS2A is the end result of this TRIM52 interaction, it is unknown whether the loss in JEV replication is the result of a recovered innate immune factor that NS2A was inhibiting or a loss in JEV RNA replication due to an absent NS2A. Flavivirus non-structural proteins are a target for TRIMs as TRIM69 can identify the DENV NS3 and destroy it via the proteasome through ubiquitin labelling [77]. As part of the protease complex, NS3 combines with NS2B to form NS2B/3 which functions in cleavage of the DENV precursor polyproteins as well as escape from host immunity [77].…”

Section: Proteasome-dependent Antiviral Mechanismsmentioning

confidence: 99%

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To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Hage

Rajsbaum

2019

Journal of General Virology

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The innate immune system responds rapidly to protect against viral infections, but an overactive response can cause harmful damage. To avoid this, the response is tightly regulated by post-translational modifications (PTMs). The ubiquitin system represents a powerful PTM machinery that allows for the reversible linkage of ubiquitin to activate and deactivate a target's function. A precise enzymatic cascade of ubiquitin-activating, conjugating and ligating enzymes facilitates ubiquitination. Viruses have evolved to take advantage of the ubiquitin pathway either by targeting factors to dampen the antiviral response or by hijacking the system to enhance their replication. The tripartite motif (TRIM) family of E3 ubiquitin ligases has garnered attention as a major contributor to innate immunity. Many TRIM family members limit viruses either indirectly as components in innate immune signalling, or directly by targeting viral proteins for degradation. In spite of this, TRIMs and other ubiquitin ligases can be appropriated by viruses and repurposed as valuable tools in viral replication. This duality of function suggests a new frontier of research for TRIMs and raises new challenges for discerning the subtleties of these pro-viral mechanisms. Here, we review current findings regarding the involvement of TRIMs in host-virus interactions. We examine ongoing developments in the field, including novel roles for unanchored ubiquitin in innate immunity, the direct involvement of ubiquitin ligases in promoting viral replication, recent controversies on the role of ubiquitin and TRIM25 in activation of the pattern recognition receptor RIG-I, and we discuss the implications these studies have on future research directions.

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Section: Proteasome-dependent Antiviral Mechanismsmentioning

confidence: 99%

“…The importance of TRIM69 in countering DENV can not only be attributed to the loss of NS3, but also to the recovery of innate immune factors targeted by NS2B/3. Indeed, expression of TRIM69 can reduce the NS2B/3-mediated cleavage of STING [77].…”

Section: Proteasome-dependent Antiviral Mechanismsmentioning

confidence: 99%

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

Hage

Rajsbaum

2019

Journal of General Virology

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“…Meta-analysis of these data indicated that TRIM69 expression was upregulated ~10-fold, following IFN-stimulation of primary human fibroblasts (Figure 2A). Similarly, TRIM69 has previously been identified as an ISG in multiple studies, and is typically induced between ~2 and ~10-fold by type I IFNs (2, 32). To examine whether the endogenous protein exhibited antiviral activity, we knocked out TRIM69 using CRISPR/Cas9 in diploid CADOES1 cells (33).…”

Section: Resultsmentioning

confidence: 81%

TRIM69 inhibits Vesicular Stomatitis Indiana Virus (VSIV)

Rihn¹,

Aziz²,

Stewart³

et al. 2019

Preprint

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word count: 210 16 Text character count: 58,351 17 18 ABSTRACT 19Vesicular Stomatitis Indiana Virus (VSIV) is a model virus that is exceptionally 20 sensitive to the inhibitory action of interferons. Interferons induce an antiviral state by 21 stimulating the expression of hundreds of interferon stimulated genes (ISGs). These 22 ISGs constrain viral replication, limit tissue tropism, reduce pathogenicity and inhibit 23 viral transmission. Because VSIV is used as a backbone for multiple oncolytic and 24 vaccine strategies, understanding how ISGs restrict VSIV, not only helps in 25 understanding VSIV-pathogenesis, but helps evaluate and understand the safety and 26 efficacy of VSIV-based therapies. Thus there is a need to identify and characterize 27 the ISGs that possess anti-VSIV activity. Using arrayed ISG expression screening, 28 solely responsible for limiting VSIV replication in other organs (15). Thus, other ISGs 85 must play key roles in limiting VSIV tissue tropism. Importantly, VSIV causes 86 neurological disease in multiple species following intracranial inoculation (17, 18), 87suggesting that the ability of ISGs to prevent VSIV from initially accessing the CNS is 88 the cornerstone in limiting VSIV neuropathology across multiple species (19). 89VSIV's low pathogenicity in humans, its rapid replication, and ease of genetic 90 manipulation have made this virus the basis of multiple therapeutic strategies. For 91 example, VSIV can be modified to express antigens from heterologous viruses that 92 can be utilised as vaccine strategies (20). This approach has achieved recent notable 93 success in conferring protection from Ebola virus infection (21). Similarly, VSIV has 94 been used as the backbone of multiple oncolytic strategies (22). Just like natural 95 VSIV infection, IFNs and ISGs appear to be critical for preventing oncolytic viruses 96 from invading healthy tissues (23, 24) and could be critical determinants governing 97 whether oncolytic vesiculoviruses will be efficacious (25). Furthermore, ISGs likely 98 play a key role in limiting the replication of VSIV-based vaccines and are an 99 important safety feature of this immunization strategy. 100The key roles that ISGs play in constraining VSIV pathogenesis and limiting 101 VSIV replication (in natural infection, oncolytic therapies and vaccine strategies) 102 means there is a need to better understand how ISGs inhibit VSIV. Using arrayed 103 ISG expression screening, we identified that TRIM69, a relatively poorly 104 characterised TRIM protein, has anti-VSIV activity. Through exogenous expression 105 and CRISPR Cas9 knockout, we demonstrate that both exogenous and endogenous 106 TRIM69 have potent anti-VSIV activity. Importantly, the inhibition is highly specific 107 for VSIV and multiple other viruses were not inhibited by TRIM69. Notably, TRIM69 108 shows strong signatures of positive selection and multiple common alleles circulate in 109 human populations. Interestingly, murine orthologues of TRIM69 had no detectable 110 anti-VSIV activity whereas ...

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“…TRIM69 joins a growing list of TRIM proteins that have been shown to exhibit antiviral activity through various mechanisms (12). During the course of this work, TRIM69 itself was reported to inhibit Dengue virus replication, albeit via a different mechanism to that described herein, namely ubiquitin-induced degradation of the viral NS3 RNA helicase (25). Other examples of antiviral TRIM proteins include TRIM5a, which inhibits early stages of retroviral infection by binding in a polyvalent manner to incoming retroviral capsids, promoting premature uncoating and degradation of virion components (26,27).…”

Section: Discussionmentioning

confidence: 84%

Vesicular stomatitis virus transcription is inhibited by TRIM69 in the interferon-induced antiviral state

Kueck

Bloyet

Cassella

et al. 2019

Preprint

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Interferons (IFNs) induce the expression of many interferon stimulated genes (ISGs), many of which are responsible for the cellular 'antiviral state' in which the replication of numerous viruses is blocked. How the majority of individual ISGs inhibit the replication of particular viruses is unknown. We conducted a loss-of-function screen to identify genes required for the activity of IFNa against vesicular stomatitis virus, Indiana serotype (VSVIND), a prototype negative strand RNA virus. Our screen revealed that TRIM69, a member of tripartite motif family of proteins, is a VSVIND inhibitor. TRIM69 potently inhibited VSVIND replication through a previously undescribed transcriptional inhibition mechanism. Specifically, TRIM69 physically associates with the VSVIND phosphoprotein (P), requiring a specific peptide target sequence encoded therein. P is a cofactor for the viral polymerase, and is required for viral RNA synthesis as well as the assembly of replication compartments. By targeting P, TRIM69 inhibits pioneer transcription of the incoming virion-associated minus strand RNA, thereby preventing the synthesis of viral mRNAs, and consequently impedes all downstream events in the VSVIND replication cycle.

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Interferon-stimulated TRIM69 interrupts dengue virus replication by ubiquitinating viral nonstructural protein 3

Cited by 77 publications

References 68 publications

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

To TRIM or not to TRIM: the balance of host–virus interactions mediated by the ubiquitin system

TRIM69 inhibits Vesicular Stomatitis Indiana Virus (VSIV)

Vesicular stomatitis virus transcription is inhibited by TRIM69 in the interferon-induced antiviral state

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