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Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function.

ABSTRACT: The human tripartite motif (TRIM) family comprises 70 members, including HIV restriction factor TRIM5alpha and disease-associated proteins TRIM20 (pyrin) and TRIM21. TRIM proteins have conserved domain architecture but diverse cellular roles. Here, we describe how the C-terminal PRYSPRY domain mediates diverse TRIM functions. The crystal structure of TRIM21 PRYSPRY in complex with its target IgG Fc reveals a canonical binding interface comprised of two discrete pockets formed by antibody-like variable loops. Alanine scanning of this interface has identified the hot-spot residues that control TRIM21 binding to Fc; the same hot-spots control HIV/murine leukemia virus restriction by TRIM5alpha and mediate severe familial Mediterranean fever in TRIM20/pyrin. Characterization of the IgG binding site for TRIM21 PRYSPRY reveals TRIM21 as a superantigen analogous to bacterial protein A and suggests that an antibody bipolar bridging mechanism may contribute to the pathogenic accumulation of anti-TRIM21 autoantibody immune complex in autoimmune disease.

SUBMITTER: James LC

PROVIDER: S-EPMC1851072 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function.

James Leo C LC Keeble Anthony H AH Khan Zahra Z Rhodes David A DA Trowsdale John J

Proceedings of the National Academy of Sciences of the United States of America 20070330 15

The human tripartite motif (TRIM) family comprises 70 members, including HIV restriction factor TRIM5alpha and disease-associated proteins TRIM20 (pyrin) and TRIM21. TRIM proteins have conserved domain architecture but diverse cellular roles. Here, we describe how the C-terminal PRYSPRY domain mediates diverse TRIM functions. The crystal structure of TRIM21 PRYSPRY in complex with its target IgG Fc reveals a canonical binding interface comprised of two discrete pockets formed by antibody-like va ...[more]

PMID: 17400754

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Project description:BackgroundThe tripartite motif (TRIM) family are important members of the Gene-finger-containing E3 ubiquitin-conjugating enzyme and are involved in the progression of hepatocellular carcinoma (HCC). Previous studies have largely focused on gene expression and molecular pathways, while the underlying role of the TRIM family in the tumor immune microenvironment (TIME) remains poorly understood.MethodsWe systematically explored the correlations of prominent TRIM genes with immune checkpoints and immune infiltrates in 231 HCC samples [International Cancer Genome Consortium (ICGC) cohort (n=231); The Cancer Genome Atlas (TCGA) cohort (n=370)]. A prognostic risk model was constructed using the least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression analysis in the ICGC cohort. Kaplan-Meier curves based on the overall survival (OS) were used to assess differences in survival between clusters. We utilized gene set variation analysis (GSVA) to characterize the differences in biological functions. Based on univariate and multivariate Cox progression analysis, we developed a risk score signature and verified its reliability and validity. The Tumor Immune Single-cell Hub (TISCH) single-cell database was employed to evaluate the correlation of TRIM genes with the tumor microenvironment.ResultsCluster 1 was preferentially associated with a favorable prognosis (P<0.001). The amino acid, fatty acid, and drug metabolism pathways were significantly enriched in cluster 2. A prognosis risk score project was established and evaluated based on the 9 independent prognostic genes (all P<0.05). The immune score and stromal scores of patients with low-risk scores were greater than those of patients with high-risk scores (all P<0.001). However, patients with a high-risk score exhibited lower responses to immune check-point inhibitors (ICIs), sorafenib, and transarterial chemoembolization (TACE) treatment (all P<0.05). Consistently, TRIM genes showed the same influence in the external TCGA cohort. TRIM gene-based signatures were implicated in TIME and their copy-number alterations dynamically impacted the abundance of tumor-infiltrating immune cells.ConclusionsOur findings revealed that MID1, TRIM5, TRIM22, TRIM28, TRIM 31, TRIM37, TRIM38, TRIM47, and TRIM74 could serve as efficient prognostic biomarkers and therapeutic targets in HCC. The identified TRIM gene-based signatures could serve as important TIME mediators in HCC, potentially increasing immune treatment efficacy.

Project description:BackgroundTripartite motif (TRIM) family genes get involved in the pathogenesis and development of various biological processes; however, the prognostic value of TRIM genes for idiopathic pulmonary fibrosis (IPF) needs to be explored.MethodsWe acquired gene expression based on bronchoalveolar lavage (BAL) cells and clinical data of three independent IPF cohorts in the GSE70866 dataset from the Gene expression omnibus (GEO) database. Differentially expressed TRIM genes (DETGs) between IPF patients and healthy donors were identified and used to establish a risk signature by univariate and multivariate Cox regression analysis in the training cohort. The risk signature was further validated in other IPF cohorts, and compared with previously published signatures. Moreover, we performed functional enrichment analysis to explore the potential mechanisms. Eventually, the quantitative real time PCR was conducted to validate the expressions of the key genes in BAL from 12 IPF patients and 12 non-IPF controls from our institution.ResultsWe identified 4 DETGs including TRIM7, MEFV, TRIM45 and TRIM47 significantly associated with overall survival (OS) of IPF patients (P < 0.05). A multiple stepwise Cox regression analysis was performed to construct a 4-TRIM-gene prognostic signature. We categorized IPF patients into one low-risk group and the other high-risk group as per the average risk value of the TRIM prognostic signature in the training and validation cohorts. The IPF individuals in the low-risk group demonstrated an obvious OS advantage compared with the high-risk one (P < 0.01). The time-dependent receiver operating characteristic approach facilitated the verification of the predictive value of the TRIM prognostic signature in the training and validation cohorts, compared with other published signatures. A further investigation of immune cells and IPF survival displayed that higher proportion of resting memory CD4+ T cells and resting mast cells harbored OS advantage over lower proportion, however lower proportion of neutrophils, activated dendritic cells and activated NK cells indicated worse prognosis.ConclusionThe TRIM family genes are significant for the prognosis of IPF and our signature could serve as a robust model to predict OS.

Project description:BackgroundThe Tripartite motif (TRIM) family includes more than 80 distinct human genes. Their function has been implicated in regulating important cellular processes, including intracellular signaling, transcription, autophagy, and innate immunity. During viral infections, macrophages are key components of innate immunity that produce interferons (IFNs) and IL27. We recently published that IL27 and IFNs induce transcriptional changes in various genes, including those involved in JAK-STAT signaling. Furthermore, IL27 and IFNs share proinflammatory and antiviral pathways in monocyte-derived macrophages (MDMs), resulting in both common and unique expression of inflammatory factors and IFN-stimulated genes (ISGs) encoding antiviral proteins. Interestingly, many TRIM proteins have been recognized as ISGs in recent years. Although it is already very well described that TRIM expression is induced by IFNs, it is not fully understood whether TRIM genes are induced in macrophages by IL27. Therefore, in this study, we examined the effect of stimulation with IL27 and type I, II, and III IFNs on the mRNA expression profiles of TRIM genes in MDMs.MethodsWe used bulk RNA-seq to examine the TRIM expression profile of MDMs treated with IFNs or IL27. Initially, we characterized the expression patterns of different TRIM subfamilies using a heatmap. Subsequently, a volcano plot was employed to identify commonly differentially expressed TRIM genes. Additionally, we conducted gene ontology analysis with ClueGO to explore the biological processes of the regulated TRIMs, created a gene-gene interaction network using GeneMANIA, and examined protein-protein interactions with the STRING database. Finally, RNA-seq data was validated using RT-qPCR. Furthermore, the effect of IL27 on Mayaro virus replication was also evaluated.ResultsWe found that IL27, similar to IFNs, upregulates several TRIM genes' expression in human macrophages. Specifically, we identified three common TRIM genes (TRIM19, 21, and 22) induced by IL27 and all types of human IFNs. Additionally, we performed the first report of transcriptional regulation of TRIM19, 21, 22, and 69 genes in response to IL27. The TRIMs involved a broad range of biological processes, including defense response to viruses, viral life cycle regulation, and negative regulation of viral processes. In addition, we observed a decrease in Mayaro virus replication in MDMs previously treated with IL27.ConclusionsOur results show that IL27, like IFNs, modulates the transcriptional expression of different TRIM-family members involved in the induction of innate immunity and an antiviral response. In addition, the functional analysis demonstrated that, like IFN, IL27 reduced Mayaro virus replication in MDMs. This implies that IL27 and IFNs share many similarities at a functional level. Moreover, identifying distinct TRIM groups and their differential expressions in response to IL27 provides new insights into the regulatory mechanisms underlying the antiviral response in human macrophages.

Dataset Information

Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function.

Publications

Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function.

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