14-3-3 scaffold proteins mediate the inactivation of trim25 and inhibition of the type I interferon response by herpesvirus deconjugases

Gupta, Soham; Ylä-Anttila, Päivi; Sandalova, Tatyana; Sun, Renhua; Achour, Adnane; Masucci, Maria G.

doi:10.1371/journal.ppat.1008146

Cited by 44 publications

(55 citation statements)

References 60 publications

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“…Such an inter-dimer association could also be facilitated by RNA binding, especially through enrichment in RNA granules leading to high concentrations. Alternative models have been proposed, that place the RING domain closer to the center of the CC, allowing for RING dimerization within the TRIM25 dimer (47,59) We note that our proposed mechanism of TRIM25 activation resembles the mechanism of RNA dependent regulation of the E3-ubiquitin ligase activity of roquins (60): Roquins feature two rigid multidomain motifs, that are connected by a flexible linker and both bind RNA. RNA binding therefore removes flexibility from the system and forces the protein into an active conformation.…”

Section: Discussionmentioning

confidence: 85%

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: Discussionmentioning

confidence: 85%

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

Haubrich

Augsten²,

Álvarez³

et al. 2020

Preprint

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show abstract

“…Epstein-Barr virus (EBV) encodes a large tegument protein BPLF1, a viral deubiquitinase (DUB) that facilitates TRIM25's interaction with the 14-3-3 scaffold to promote TRIM25 autoubiquitination and sequestration to inhibit IFN-I responses [106].…”

Section: Antagonism Of Trim25-mediated Ifn Induction By Denv Mers-comentioning

confidence: 99%

TRIM Proteins in Host Defense and Viral Pathogenesis

Giraldo

Hage

Tol

et al. 2020

Curr Clin Micro Rpt

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Purpose of Review Tripartite motif (TRIM) proteins are a large group of E3 ubiquitin ligases involved in different cellular functions. Of special interest are their roles in innate immunity, inflammation, and virus replication. We discuss novel roles of TRIM proteins during virus infections that lead to increased pathogenicity. Recent Findings TRIM proteins regulate different antiviral and inflammatory signaling pathways, mostly by promoting ubiquitination of important factors including pattern recognition receptors, adaptor proteins, kinases, and transcription factors that are involved in type I interferon and NF-κB pathways. Therefore, viruses have developed mechanisms to target TRIMs for immune evasion. New evidence is emerging indicating that viruses have the ability to directly use TRIMs and the ubiquitination process to enhance the viral replication cycle and cause increased pathogenesis. A new report on TRIM7 also highlights the potential pro-viral role of TRIMs via ubiquitination of viral proteins and suggests a novel mechanism by which ubiquitination of virus envelope protein may provide determinants of tissue and species tropism. Summary TRIM proteins have important functions in promoting host defense against virus infection; however, viruses have adapted to evade TRIM-mediated immune responses and can hijack TRIMs to ultimately increase virus pathogenesis. Only by understanding specific TRIM-virus interactions and by using more in vivo approaches can we learn how to harness TRIM function to develop therapeutic approaches to reduce virus pathogenesis.

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“…3f). Additionally, co-overexpression of OTUD5 inhibited TRIM25 ubiquitination, phenocopying the TRIM25 K117R mutant, which was missing an important TRIM25 autoubiquitination site 52 , implying that OTUD5 played a crucial role in TRIM25 autoubiquitination (Supplementary Fig. 2A).…”

Section: Depletion Of Otud5 Dramatically Promotes Cell Proliferationmentioning

confidence: 96%

OTUD5 cooperates with TRIM25 in transcriptional regulation and tumor progression via deubiquitination activity

Sun

Liu

et al. 2020

Nat Commun

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Oncogenic processes exert their greatest effect by targeting regulators of cell proliferation. Studying the mechanism underlying growth augmentation is expected to improve clinical therapies. The ovarian tumor (OTU) subfamily deubiquitinases have been implicated in the regulation of critical cell-signaling cascades, but most OTUs functions remain to be investigated. Through an unbiased RNAi screen, knockdown of OTUD5 is shown to significantly accelerate cell growth. Further investigation reveals that OTUD5 depletion leads to the enhanced transcriptional activity of TRIM25 and the inhibited expression of PML by altering the ubiquitination level of TRIM25. Importantly, OTUD5 knockdown accelerates tumor growth in a nude mouse model. OTUD5 expression is markedly downregulated in tumor tissues. The reduced OTUD5 level is associated with an aggressive phenotype and a poor clinical outcome for cancers patients. Our findings reveal a mechanism whereby OTUD5 regulates gene transcription and suppresses tumorigenesis by deubiquitinating TRIM25, providing a potential target for oncotherapy.

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14-3-3 scaffold proteins mediate the inactivation of trim25 and inhibition of the type I interferon response by herpesvirus deconjugases

Cited by 44 publications

References 60 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

TRIM Proteins in Host Defense and Viral Pathogenesis

OTUD5 cooperates with TRIM25 in transcriptional regulation and tumor progression via deubiquitination activity

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