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The molecular dissection of TRIM25‘s RNA-binding mechanism provides key insights into its antiviral activity

ABSTRACT: TRIM25 is an RNA-binding ubiquitin E3 ligase with central but poorly understood roles in the innate immune response to RNA viruses. The link between TRIM25’s RNA binding and its role in innate immunity has not been established. Thus, we utilized a multitude of biophysical techniques to identify key RNA-binding residues of TRIM25 and developed an RNA-binding deficient mutant (TRIM25-m9). Using iCLIP2 in virus-infected and uninfected cells, we identified TRIM25’s RNA sequence and structure specificity, that it binds specifically to viral RNA, and that the interaction with RNA is critical for its antiviral activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE276465 | GEO | 2024/09/20

REPOSITORIES: GEO

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TRIM25

Project description:TRIM25

| PRJNA316328 | ENA

RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination

Project description:TRIM25 is a novel RNA-binding protein and a member of the Tripartite Motif (TRIM) family of E3 ubiquitin ligases, which plays a pivotal role in the innate immune response. Almost nothing is known about its RNA-related roles in cell biology. Furthermore, its RNA-binding domain has not been characterized. Here, we reveal that RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain, which we postulate to be a novel RNA-binding domain. Using CLIP-seq and SILAC-based co-immunoprecipitation assays, we uncover TRIM25’s endogenous RNA targets and protein binding partners. Finally, we show that the RNAbinding activity of TRIM25 is important for its ubiquitin ligase function. These results reveal new insights into the molecular roles and characteristics of RNA-binding E3 ubiquitin ligases and demonstrate that RNA could be an essential factor for their biological functions.

2017-10-19 | PXD007960 | Pride

RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination

Project description:TRIM25 E3 ubiquitin ligase is a new RNA-binding protein. We present the first high-throughput analysis of the molecular interactomes of TRIM25. We show that TRIM25 is a bona fide RNA-binding protein that interacts with numerous coding and non-coding transcripts. This suggests that TRIM25 could play a role in the regulation of RNA metabolism.

2018-07-27 | GSE104949 | GEO

Genome-wide maps of TRIM25 binding sites in triple negative breast cancer cell

Project description:We report high-throughput profiling of TRIM25 binding sites in triple negative breast cancer cells.

2017-04-01 | GSE79588 | GEO

The E3 ligase TRIM25 impairs apoptotic cell death in colon carcinoma cells through hnRNPH1-triggered destabilization of caspase-7 mRNA

Project description:Therapy resistance is still a major reason for treatment failure in colorectal cancer (CRC). Previously, we identified the E3 ubiquitin ligase TRIM25 as a novel suppressor of caspase-2 translation, thereby contributing to apoptosis resistance of CRC cells towards chemotherapeutic drugs. We herein report the executioner caspase-7 being a further target of TRIM25. Results from gain and loss-of-function approaches and actinomycin D experiments indicate that TRIM25 attenuates caspase-7 expression mainly through a decrease in mRNA stability. Data from RNA pull-down assays with immunoprecipitated TRIM25 truncations indicate a direct TRIM25 binding to caspase-7 mRNA which is mediated by the PRY/SPRY domain which is also known to be highly relevant for protein-protein interactions. By employing TRIM25 immunoprecipitation, we identified the heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1) as a novel TRIM25 binding protein involved in the control of caspase-7 mRNA stability. Notably, the interaction of both proteins was highly sensitive to RNase A treatment and again depended on the PRY/SPRY domain, thus indicating an indirect interaction of both proteins which is achieved through a common RNA binding. Ubiquitin affinity chromatography showed that hnRNPH1 and TRIM25 are targets of ubiquitin modification. Functionally, the ectopic expression of caspase-7 in CRC cells caused an increase in poly ADP-ribose polymerase (PARP) cleavage concomitant with a significant increase in apoptosis. Collectively, the negative regulation of caspase-7 by TRIM25 via hnRNPH1 implies a novel survival mechanism underlying chemotherapeutic drug resistance of CRC cells. Targeting of TRIM25 could therefore offer a promising strategy for reducing therapy resistance in CRC patients.

2023-01-05 | PXD037182 | Pride

The molecular dissection of TRIM25‘s RNA-binding mechanism provides key insights into its antiviral activity

Project description:The molecular dissection of TRIM25‘s RNA-binding mechanism provides key insights into its antiviral activity

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Substrate trapping approach identifies TRIM25 ubiquitination targets involved in diverse cellular and antiviral processes

Project description:The tripartite motif (TRIM) family of E3 ubiquitin ligases is well known for its roles in antiviral restriction and innate immunity regulation, in addition to many other cellular pathways. In particular, TRIM25-mediated ubiquitination affects both carcinogenesis and antiviral response. While individual substrates have been identified for TRIM25, it remains unclear how it regulates diverse processes. Here we characterized a mutation, R54P, critical for TRIM25 catalytic activity, which we successfully utilized to “trap” substrates. We demonstrated that TRIM25 targets proteins implicated in stress granule formation (G3BP1/2), nonsense-mediated mRNA decay (UPF1), and nucleoside synthesis (NME1). R54P abolishes TRIM25 inhibition of alphaviruses independently of the host interferon response, suggesting that this antiviral effect is a direct consequence of ubiquitination. Consistent with that, we observed diminished antiviral activity upon knockdown of several TRIM25-R54P specific interactors including NME1. Our findings highlight that multiple substrates mediate the cellular and antiviral activities of TRIM25, illustrating the multi-faceted role of this ubiquitination network in diverse biological processes.

2022-08-02 | PXD034024 | Pride

Effect of depletion of TRIM25 and inhibition of p300 on gene expression in breast cancer cells

Project description:To analyze the effect of TRIM25 on gene expression, TRIM25 was knocked out in MCF7 cells. To understand a possible contribution of p300 on this gene regulation, p300 was inhibited. RNA seq was performed to see changes in the whole transcriptome

2022-10-11 | GSE215084 | GEO

The long noncoding RNA Lnczc3h7a promotes TRIM25-mediated RIG-I antiviral innate immune response

Project description:The long noncoding RNA Lnczc3h7a promotes TRIM25-mediated RIG-I antiviral innate immune response

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TRIM25 promotes glioblastoma cell growth and invasion via regulation of the PRMT1/c-MYC pathway by targeting the splicing factor NONO

Project description:Ubiquitination plays an important role in proliferating and invasive characteristic of glioblastoma (GBM), similar to many other cancers. Tripartite motif 25 (TRIM25) is a member of the TRIM family of proteins, which are involved in tumorigenesis through substrate ubiquitination. Here, we found TRIM25 is upregulated in GBM and promotes glioblastoma cell growth and invasion, both in vitro and in vivo. Subsequently, we screened a panel of proteins that interact with TRIM25; mass spectrometry and co-immunoprecipitation showed that NONO was a potential substrate of TRIM25. TRIM25 knockdown reduced the K63-linked ubiquitination of NONO, which suppressed the splicing function of NONO. The dysfunctional NONO further leads to the retention of the second intron in the pre-mRNA of PRMT1 and inhibit the activation of the PRMT1/c-MYC pathway. In summary, we demonstrated that TRIM25 promotes glioblastoma cell growth and invasion by regulating the PRMT1/c-MYC pathway through mediation of the splicing factor NONO. Efforts to target the E3 ligase activity of TRIM25 or the complex interactions between TRIM25 and NONO may be useful in the treatment of GBM.

2023-07-11 | GSE236661 | GEO

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