TRIM25 Binds RNA to Modulate Cellular Anti-viral Defense

Sanchez, Jacint G.; Sparrer, Konstantin M. J.; Chiang, Cindy; Reis, Rebecca; Chiang, Jessica J.; Zurenski, Matthew A.; Wan, Yuqing; Gack, Michaela U.; Pornillos, Owen

doi:10.1016/j.jmb.2018.10.003

Cited by 75 publications

(108 citation statements)

References 28 publications

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“…As reported previously, we found that the affinity of the PRY/SPRY domain for pre-let-7 RNA (5.0±1.2 µM, as measured by ITC, Table 2, Figure 2B) is much weaker than for CC-PRY/SPRY (25,26). The RNA-binding of the PRY/SPRY domain alone is therefore not sufficient to explain the high affinity binding of TRIM25.…”

Section: Two Distinct Sites Of the Trim25 Pry/spry Domain Bind To Sinsupporting

confidence: 58%

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

Haubrich

Augsten²,

Álvarez³

et al. 2020

Preprint

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TRIM25 is a ubiquitin E3 ligase active in innate immunity and cell fate decisions. Mounting evidence suggests that TRIM25’s E3 ligase activity is regulated by RNAs. However, while mutations affecting RNA-binding have been described, the precise RNA binding site has not been identified nor which domains are involved. Here, we present biophysical evidence for the presence of RNA binding sites on both TRIM25 PRY/SPRY and coiled-coil domains, and map the binding site on the PRY/SPRY with residue resolution. Cooperative RNA-binding of both domains enhances their otherwise transient interaction in solution and increases the E3 ligase activity of TRIM25. Mutational analysis shows that RNA binding affects ubiquitination of RIG-I in mammalian cells. In addition, we present a simple model system for RNA-induced liquid-liquid phase separation of TRIM25 in vitro, resembling previously observed cellular RNA granules, that facilitates the recruitment of RIG-I.

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Section: Two Distinct Sites Of the Trim25 Pry/spry Domain Bind To Sinsupporting

confidence: 58%

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

Haubrich

Augsten²,

Álvarez³

et al. 2020

Preprint

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“…However, other cellular factors present could modulate ZAP's binding specificity. Several groups have shown that the ZAP cofactor TRIM25 can bind cellular and viral RNA, and it has been reported to regulate ZAP binding to Sindbis virus RNA (29,30,(60)(61)(62)(63)(64)(65). Therefore, TRIM25 or other ZAP cofactors could bind specific motifs in viral RNA to determine the sensitivity of the RNA to ZAP-mediated antiviral activity.…”

Section: Discussionmentioning

confidence: 99%

CpG Dinucleotides Inhibit HIV-1 Replication through Zinc Finger Antiviral Protein (ZAP)-Dependent and -Independent Mechanisms

Ficarelli

Antzin-Anduetza

Hugh-White

et al. 2020

J Virol

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CpG dinucleotides are suppressed in the genomes of many vertebrate RNA viruses, including HIV-1. The cellular antiviral protein ZAP (zinc finger antiviral protein) binds CpGs and inhibits HIV-1 replication when CpGs are introduced into the viral genome. However, it is not known if ZAP-mediated restriction is the only mechanism driving CpG suppression. To determine how CpG dinucleotides affect HIV-1 replication, we increased their abundance in multiple regions of the viral genome and analyzed the effect on RNA expression, protein abundance, and infectious-virus production. We found that the antiviral effect of CpGs was not correlated with their abundance. Interestingly, CpGs inserted into some regions of the genome sensitize the virus to ZAP antiviral activity more efficiently than insertions into other regions, and this sensitivity can be modulated by interferon treatment or ZAP overexpression. Furthermore, the sensitivity of the virus to endogenous ZAP was correlated with its sensitivity to the ZAP cofactor KHNYN. Finally, we show that CpGs in some contexts can also inhibit HIV-1 replication by ZAP-independent mechanisms, and one of these is the activation of a cryptic splice site at the expense of a canonical splice site. Overall, we show that the location and sequence context of the CpG in the viral genome determines its antiviral activity. IMPORTANCE Some RNA virus genomes are suppressed in the nucleotide combination of a cytosine followed by a guanosine (CpG), indicating that they are detrimental to the virus. The antiviral protein ZAP binds viral RNA containing CpGs and prevents the virus from multiplying. However, it remains unknown how the number and position of CpGs in viral genomes affect restriction by ZAP and whether CpGs have other antiviral mechanisms. Importantly, manipulating the CpG content in viral genomes could help create new vaccines. HIV-1 shows marked CpG suppression, and by introducing CpGs into its genome, we show that ZAP efficiently targets a specific region of the viral genome, that the number of CpGs does not predict the magnitude of antiviral activity, and that CpGs can inhibit HIV-1 gene expression through a ZAP-independent mechanism. Overall, the position of CpGs in the HIV-1 genome determines the magnitude and mechanism through which they inhibit the virus.

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“…Upon induction, some lncRNAs and miRNAs promote or dampen RLR signalling by regulating the gene expression of RLRs or other key molecules in the RLR pathway. In addition, some lncRNAs were shown to directly bind to the RLR sensor protein (in particular RIG-I), or its activator TRIM25, which itself has RNA-binding capacity 101,147,148 (fiG. 4).…”

Section: Regulation By Non-coding Rnas Cellular Non-codingmentioning

confidence: 99%

“…Although RIG-I is well known to be a bona fide RNA sensor, its activator, TRIM25, has recently been shown to also have RNA-binding capacity 101,147,148 . Biochemical and functional studies showed that the ability of TRIM25 to bind RNA is important for its E3 ligase activity and, thus, its positive effect on RIG-I antiviral signalling 148…”

Section: Regulation By Non-coding Rnas Cellular Non-codingmentioning

confidence: 99%

RIG-I-like receptors: their regulation and roles in RNA sensing

2020

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| Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are key sensors of virus infection, mediating the transcriptional induction of type I interferons and other genes that collectively establish an antiviral host response. Recent studies have revealed that both viral and host-derived RNAs can trigger RLR activation; this can lead to an effective antiviral response but also immunopathology if RLR activities are uncontrolled. In this Review , we discuss recent advances in our understanding of the types of RNA sensed by RLRs in the contexts of viral infection, malignancies and autoimmune diseases. We further describe how the activity of RLRs is controlled by host regulatory mechanisms, including RLR-interacting proteins, post-translational modifications and non-coding RNAs. Finally , we discuss key outstanding questions in the RLR field, including how our knowledge of RLR biology could be translated into new therapeutics.

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TRIM25 Binds RNA to Modulate Cellular Anti-viral Defense

Cited by 75 publications

References 28 publications

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25

CpG Dinucleotides Inhibit HIV-1 Replication through Zinc Finger Antiviral Protein (ZAP)-Dependent and -Independent Mechanisms

RIG-I-like receptors: their regulation and roles in RNA sensing

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