Journal articles: 'TRIM protein'

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Yap, Melvyn W., Mark P. Dodding, and Jonathan P. Stoye. "Trim-Cyclophilin A Fusion Proteins Can Restrict Human Immunodeficiency Virus Type 1 Infection at Two Distinct Phases in the Viral Life Cycle." Journal of Virology 80, no. 8 (April 15, 2006): 4061–67. http://dx.doi.org/10.1128/jvi.80.8.4061-4067.2006.

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ABSTRACT The Trim5α protein from several primates restricts retroviruses in a capsid (CA)-dependent manner. In owl monkeys, the B30.2 domain of Trim5 has been replaced by cyclophilin A (CypA) following a retrotransposition. Restriction of human immunodeficiency virus type 1 (HIV-1) by the resulting Trim5-CypA fusion protein depends on CA binding to CypA, suggesting both that the B30.2 domain might be involved in CA binding and that the tripartite RING motif, B-BOX, and coiled coil (RBCC) motif domain can function independently of the B30.2 domain in restriction. To investigate the potential of RBCCs from other Trims to participate in restricting HIV-1, CypA was fused to the RBCC of Trim1, Trim18, and Trim19 and tested for restriction. Despite low identity within the RBCC domain, all fusion proteins were found to restrict HIV-1 but not the nonbinding G89V mutant, indicating that the overall structure of RBCC and not its primary sequence was important for the restriction function. The critical interaction between CA and Trim-CypA appears to take place soon after viral entry. Quantitative PCR analysis of viral reverse transcriptase products revealed that the different fusion proteins block HIV-1 at two distinct stages of its life cycle, either prior to reverse transcription or just before integration. With Trim1 and Trim18, this timing is dependent on the length of the Trim component of the fusion protein. These observations suggest that restriction factor binding can have different mechanistic consequences.

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Esposito, Diego, Marios G. Koliopoulos, and Katrin Rittinger. "Structural determinants of TRIM protein function." Biochemical Society Transactions 45, no. 1 (February 8, 2017): 183–91. http://dx.doi.org/10.1042/bst20160325.

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Tripartite motif (TRIM) proteins constitute one of the largest subfamilies of Really Interesting New Gene (RING) E3 ubiquitin ligases and contribute to the regulation of numerous cellular activities, including innate immune responses. The conserved TRIM harbours a RING domain that imparts E3 ligase activity to TRIM family proteins, whilst a variable C-terminal region can mediate recognition of substrate proteins. The knowledge of the structure of these multidomain proteins and the functional interplay between their constituent domains is paramount to understanding their cellular roles. To date, available structural information on TRIM proteins is still largely restricted to subdomains of many TRIMs in isolation. Nevertheless, applying a combination of structural, biophysical and biochemical approaches has recently allowed important progress to be made towards providing a better understanding of the molecular features that underlie the function of TRIM family proteins and has uncovered an unexpected diversity in the link between self-association and catalytic activity.

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Xiao, Maolin, Jianjun Li, Qingyuan Liu, Xiangbiao He, Zongke Yang, and Delin Wang. "Expression and Role of TRIM2 in Human Diseases." BioMed Research International 2022 (August 23, 2022): 1–14. http://dx.doi.org/10.1155/2022/9430509.

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Tripartite motif (TRIM) protein family proteins contain more than 80 members in humans, and most of these proteins exhibit E3 ubiquitin ligase activity mediated through a RING finger domain. Their biological functions are very complex, and they perform diverse functions in cell evolution processes, such as intracellular signaling, development, apoptosis, protein quality control, innate immunity, autophagy, and carcinogenesis. Tripartite motif-containing protein 2 (TRIM2), a member of the TRIM superfamily, is an 81 kDa multidomain protein, also known as CMT2R or RNF86, located at 4q31.3. TRIM2 functions as an E3 ubiquitin ligase. Current studies have shown that TRIM2 can play roles in neuroprotection, neuronal rapid ischemic tolerance, antiviral responses, neurological diseases, etc. Moreover, based on some studies in tumors, TRIM2 regulates tumor proliferation, migration, invasion, apoptosis, and drug resistance through different mechanisms and plays a critical role in tumor occurrence and development. This review is aimed at providing a systematic and comprehensive summary of research on TRIM2 and at exploring the potential role of TRIM2 as a biomarker and therapeutic target in many kinds of human diseases.

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Fiorentini, Filippo, Diego Esposito, and Katrin Rittinger. "Does it take two to tango? RING domain self-association and activity in TRIM E3 ubiquitin ligases." Biochemical Society Transactions 48, no. 6 (November 10, 2020): 2615–24. http://dx.doi.org/10.1042/bst20200383.

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TRIM proteins form a protein family that is characterized by a conserved tripartite motif domain comprising a RING domain, one or two B-box domains and a coiled-coil region. Members of this large protein family are important regulators of numerous cellular functions including innate immune responses, transcriptional regulation and apoptosis. Key to their cellular role is their E3 ligase activity which is conferred by the RING domain. Self-association is an important characteristic of TRIM protein activity and is mediated by homodimerization via the coiled-coil region, and in some cases higher order association via additional domains of the tripartite motif. In many of the TRIM family proteins studied thus far, RING dimerization is an important prerequisite for E3 ligase enzymatic activity though the propensity of RING domains to dimerize differs significantly between different TRIMs and can be influenced by other regions of the protein.

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Eberhardt, Wolfgang, Kristina Haeussler, Usman Nasrullah, and Josef Pfeilschifter. "Multifaceted Roles of TRIM Proteins in Colorectal Carcinoma." International Journal of Molecular Sciences 21, no. 20 (October 13, 2020): 7532. http://dx.doi.org/10.3390/ijms21207532.

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Colorectal cancer (CRC) is one of the most frequently diagnosed tumor in humans and one of the most common causes of cancer-related death worldwide. The pathogenesis of CRC follows a multistage process which together with somatic gene mutations is mainly attributed to the dysregulation of signaling pathways critically involved in the maintenance of homeostasis of epithelial integrity in the intestine. A growing number of studies has highlighted the critical impact of members of the tripartite motif (TRIM) protein family on most types of human malignancies including CRC. In accordance, abundant expression of many TRIM proteins has been observed in CRC tissues and is frequently correlating with poor survival of patients. Notably, some TRIM members can act as tumor suppressors depending on the context and the type of cancer which has been assessed. Mechanistically, most cancer-related TRIMs have a critical impact on cell cycle control, apoptosis, epithelial–mesenchymal transition (EMT), metastasis, and inflammation mainly through directly interfering with diverse oncogenic signaling pathways. In addition, some recent publications have emphasized the emerging role of some TRIM members to act as transcription factors and RNA-stabilizing factors thus adding a further level of complexity to the pleiotropic biological activities of TRIM proteins. The current review focuses on oncogenic signaling processes targeted by different TRIMs and their particular role in the development of CRC. A better understanding of the crosstalk of TRIMs with these signaling pathways relevant for CRC development is an important prerequisite for the validation of TRIM proteins as novel biomarkers and as potential targets of future therapies for CRC.

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Zhang, Jing-rui, Xin-xin Li, Wan-ning Hu, and Chang-yi Li. "Emerging Role of TRIM Family Proteins in Cardiovascular Disease." Cardiology 145, no. 6 (2020): 390–400. http://dx.doi.org/10.1159/000506150.

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Ubiquitination is one of the basic mechanisms of cell protein homeostasis and degradation and is accomplished by 3 enzymes, E1, E2, and E3. Tripartite motif-containing proteins (TRIMs) constitute the largest subfamily of RING E3 ligases, with >70 current members in humans and mice. These members are involved in multiple biological processes, including growth, differentiation, and apoptosis as well as disease and tumorigenesis. Accumulating evidence has shown that many TRIM proteins are associated with various cardiac processes and pathologies, such as heart development, signal transduction, protein degradation, autophagy mediation, ion channel regulation, congenital heart disease, and cardiomyopathies. In this review, we provide an overview of the TRIM family and discuss its involvement in the regulation of cardiac proteostasis and pathophysiology and its potential therapeutic implications.

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Pauletto, Eleonora, Nils Eickhoff, Nuno Padrão, Christine Blattner, and Wilbert Zwart. "TRIMming Down Hormone-Driven Cancers: The Biological Impact of TRIM Proteins on Tumor Development, Progression and Prognostication." Cells 10, no. 6 (June 16, 2021): 1517. http://dx.doi.org/10.3390/cells10061517.

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The tripartite motif (TRIM) protein family is attracting increasing interest in oncology. As a protein family based on structure rather than function, a plethora of biological activities are described for TRIM proteins, which are implicated in multiple diseases including cancer. With hormone-driven cancers being among the leading causes of cancer-related death, TRIM proteins have been described to portrait tumor suppressive or oncogenic activities in these tumor types. This review describes the biological impact of TRIM proteins in relation to hormone receptor biology, as well as hormone-independent mechanisms that contribute to tumor cell biology in prostate, breast, ovarian and endometrial cancer. Furthermore, we point out common functions of TRIM proteins throughout the group of hormone-driven cancers. An improved understanding of the biological impact of TRIM proteins in cancer may pave the way for improved prognostication and novel therapeutics, ultimately improving cancer care for patients with hormone-driven cancers.

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Aizaz, Muhammad, Yusra Sajid Kiani, Maryum Nisar, Shijuan Shan, Rehan Zafar Paracha, and Guiwen Yang. "Genomic Analysis, Evolution and Characterization of E3 Ubiquitin Protein Ligase (TRIM) Gene Family in Common Carp (Cyprinus carpio)." Genes 14, no. 3 (March 7, 2023): 667. http://dx.doi.org/10.3390/genes14030667.

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Tripartite motifs (TRIM) is a large family of E3 ubiquitin ligases that play an important role in ubiquitylation. TRIM proteins regulate a wide range of biological processes from cellular response to viral infection and are implicated in various pathologies, from Mendelian disease to cancer. Although the TRIM family has been identified and characterized in tetrapods, but the knowledge about common carp and other teleost species is limited. The genes and proteins in the TRIM family of common carp were analyzed for evolutionary relationships, characterization, and functional annotation. Phylogenetic analysis was used to elucidate the evolutionary relationship of TRIM protein among teleost and higher vertebrate species. The results show that the TRIM orthologs of highly distant vertebrates have conserved sequences and domain architectures. The pairwise distance was calculated among teleost species of TRIMs, and the result exhibits very few mismatches at aligned position thus, indicating that the members are not distant from each other. Furthermore, TRIM family of common carp clustered into six groups on the basis of phylogenetic analysis. Additionally, the analysis revealed conserved motifs and functional domains in the subfamily members. The difference in functional domains and motifs is attributed to the evolution of these groups from different ancestors, thus validating the accuracy of clusters in the phylogenetic tree. However, the intron-exon organization is not precisely similar, which suggests duplication of genes and complex alternative splicing. The percentage of secondary structural elements is comparable for members of the same group, but the tertiary conformation is varied and dominated by coiled-coil segments required for catalytic activity. Gene ontology analysis revealed that these proteins are mainly associated with the catalytic activity of ubiquitination, immune system, zinc ion binding, positive regulation of transcription, ligase activity, and cell cycle regulation. Moreover, the biological pathway analyses identified four KEGG and 22 Reactome pathways. The predicted pathways correspond to functional domains, and gene ontology which proposes that proteins with similar structures might perform the same functions.

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Azuma, Kotaro, and Satoshi Inoue. "Efp/TRIM25 and Its Related Protein, TRIM47, in Hormone-Dependent Cancers." Cells 11, no. 15 (August 8, 2022): 2464. http://dx.doi.org/10.3390/cells11152464.

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Increasing attention has been paid to the biological roles of tripartite motif-containing (TRIM) family proteins, which typically function as E3 ubiquitin ligases. Estrogen-responsive finger protein (Efp), a member of the TRIM family proteins, also known as TRIM25, was originally identified as a protein induced by estrogen and plays critical roles in promoting endocrine-related cancers, including breast cancer, endometrial cancer, and prostate cancer. The pathophysiological importance of Efp made us interested in the roles of other TRIM family proteins that share a similar structure with Efp. Based on a phylogenetic analysis of the C-terminal region of TRIM family proteins, we focused on TRIM47 as a protein belonging to the same branch as Efp. TRIM47 is a poor prognostic factor in both breast cancer and prostate cancer. Atypical lysine-27-like poly-ubiquitination was involved in the underlying mechanism causing endocrine resistance in breast cancer. We also discuss the functions of Efp and TRIM47 in other types of cancers and innate immunity by introducing substrates the are modified by poly-ubiquitination.

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Huang, Yingjie, Yue Xiao, Xuekang Zhang, Xuan Huang, and Yong Li. "The Emerging Roles of Tripartite Motif Proteins (TRIMs) in Acute Lung Injury." Journal of Immunology Research 2021 (October 19, 2021): 1–9. http://dx.doi.org/10.1155/2021/1007126.

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Acute lung injury (ALI) is an inflammatory disorder of the lung that causes high mortality and lacks any pharmacological intervention. Ubiquitination plays a critical role in the pathogenesis of ALI as it regulates the alveolocapillary barrier and the inflammatory response. Tripartite motif (TRIM) proteins are one of the subfamilies of the RING-type E3 ubiquitin ligases, which contains more than 80 distinct members in humans involved in a broad range of biological processes including antivirus innate immunity, development, and tumorigenesis. Recently, some studies have shown that several members of TRIM family proteins play important regulatory roles in inflammation and ALI. Herein, we integrate emerging evidence regarding the roles of TRIMs in ALI. Articles were selected from the searches of PubMed database that had the terms “acute lung injury,” “ubiquitin ligases,” “tripartite motif protein,” “inflammation,” and “ubiquitination” using both MeSH terms and keywords. Better understanding of these mechanisms may ultimately lead to novel therapeutic approaches by targeting TRIMs for ALI treatment.

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Bruyns, Eddy, Anne Marie-Cardine, Henning Kirchgessner, Karin Sagolla, Andrej Shevchenko, Matthias Mann, Frank Autschbach, Armand Bensussan, Stefan Meuer, and Burkhart Schraven. "T Cell Receptor (TCR) Interacting Molecule (TRIM), A Novel Disulfide-linked Dimer Associated with the TCR–CD3–ζ Complex, Recruits Intracellular Signaling Proteins to the Plasma Membrane." Journal of Experimental Medicine 188, no. 3 (August 3, 1998): 561–75. http://dx.doi.org/10.1084/jem.188.3.561.

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The molecular mechanisms regulating recruitment of intracellular signaling proteins like growth factor receptor–bound protein 2 (Grb2), phospholipase Cγ1, or phosphatidylinositol 3-kinase (PI3-kinase) to the plasma membrane after stimulation of the T cell receptor (TCR)– CD3–ζ complex are not very well understood. We describe here purification, tandem mass spectrometry sequencing, molecular cloning, and biochemical characterization of a novel transmembrane adaptor protein which associates and comodulates with the TCR–CD3–ζ complex in human T lymphocytes and T cell lines. This protein was termed T cell receptor interacting molecule (TRIM). TRIM is a disulfide-linked homodimer which is comprised of a short extracellular domain of 8 amino acids, a 19–amino acid transmembrane region, and a 159–amino acid cytoplasmic tail. In its intracellular domain, TRIM contains several tyrosine-based signaling motifs that could be involved in SH2 domain–mediated protein–protein interactions. Indeed, after T cell activation, TRIM becomes rapidly phosphorylated on tyrosine residues and then associates with the 85-kD regulatory subunit of PI3-kinase via an YxxM motif. Thus, TRIM represents a TCR-associated transmembrane adaptor protein which is likely involved in targeting of intracellular signaling proteins to the plasma membrane after triggering of the TCR.

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Esposito, Jessica Elisabetta, Vincenzo De Iuliis, Francesco Avolio, Eliana Liberatoscioli, Riccardo Pulcini, Simona Di Francesco, Alfonso Pennelli, Stefano Martinotti, and Elena Toniato. "Dissecting the Functional Role of the TRIM8 Protein on Cancer Pathogenesis." Cancers 14, no. 9 (May 6, 2022): 2309. http://dx.doi.org/10.3390/cancers14092309.

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TRIM/RBCC are a large family of proteins that include more than 80 proteins, most of which act as E3 ligases and catalyze the direct transfer of Ubiquitin, SUMO and ISG15 on specific protein substrates. They are involved in oncogenesis processes and in cellular immunity. On this topic, we focus on TRIM8 and its multiple roles in tumor pathologies. TRIM8 inhibits breast cancer proliferation through the regulation of estrogen signaling. TRIM8 downregulation in glioma is involved in cell proliferation, and it is related to patients’ survival. Several studies suggested that TRIM8 regulates the p53 suppressor signaling pathway: it is involved in the NF-kB pathway (Nuclear Factor kappa light- chain-enhancer of activated B cells) and in STAT3 (Signal Transducer and Activator of Transcription 3) of the JAK-STAT pathway. In this review, we summarize how the association between these different pathways reflects a dual role of TRIM8 in cancer as an oncogene or a tumor suppressor gene.

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Marzano, Flaviana, Mariano Francesco Caratozzolo, Graziano Pesole, Elisabetta Sbisà, and Apollonia Tullo. "TRIM Proteins in Colorectal Cancer: TRIM8 as a Promising Therapeutic Target in Chemo Resistance." Biomedicines 9, no. 3 (February 27, 2021): 241. http://dx.doi.org/10.3390/biomedicines9030241.

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Colorectal cancer (CRC) represents one of the most widespread forms of cancer in the population and, as all malignant tumors, often develops resistance to chemotherapies with consequent tumor growth and spreading leading to the patient’s premature death. For this reason, a great challenge is to identify new therapeutic targets, able to restore the drugs sensitivity of cancer cells. In this review, we discuss the role of TRIpartite Motifs (TRIM) proteins in cancers and in CRC chemoresistance, focusing on the tumor-suppressor role of TRIM8 protein in the reactivation of the CRC cells sensitivity to drugs currently used in the clinical practice. Since the restoration of TRIM8 protein levels in CRC cells recovers chemotherapy response, it may represent a new promising therapeutic target in the treatment of CRC.

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Bhaduri, Utsa, and Giuseppe Merla. "Ubiquitination, Biotech Startups, and the Future of TRIM Family Proteins: A TRIM-Endous Opportunity." Cells 10, no. 5 (April 25, 2021): 1015. http://dx.doi.org/10.3390/cells10051015.

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Ubiquitination is a post-translational modification that has pivotal roles in protein degradation and diversified cellular processes, and for more than two decades it has been a subject of interest in the biotech or biopharmaceutical industry. Tripartite motif (TRIM) family proteins are known to have proven E3 ubiquitin ligase activities and are involved in a multitude of cellular and physiological events and pathophysiological conditions ranging from cancers to rare genetic disorders. Although in recent years many kinds of E3 ubiquitin ligases have emerged as the preferred choices of big pharma and biotech startups in the context of protein degradation and disease biology, from a surface overview it appears that TRIM E3 ubiquitin ligases are not very well recognized yet in the realm of drug discovery. This article will review some of the blockbuster scientific discoveries and technological innovations from the world of ubiquitination and E3 ubiquitin ligases that have impacted the biopharma community, from biotech colossuses to startups, and will attempt to evaluate the future of TRIM family proteins in the province of E3 ubiquitin ligase-based drug discovery.

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Crunkhorn, Sarah. "TRIM family protein protects the kidney." Nature Reviews Drug Discovery 14, no. 5 (April 24, 2015): 312. http://dx.doi.org/10.1038/nrd4629.

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Chen, Yufang, Ziyan Li, Jingyao Zeng, Zhiyi Xu, and Meihua Wang. "TRIM 16 gene expression regulates the growth and metastasis of human esophageal cancer." Tropical Journal of Pharmaceutical Research 19, no. 10 (November 25, 2020): 2047–53. http://dx.doi.org/10.4314/tjpr.v19i10.4.

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Purpose: To investigate the effect of tripartite membrane protein TRIM) 16 gene silencing on human esophageal cancer (KYSE-270) cell proliferation, invasion and metastasis.Methods: Short interfering RNA (siRNA) TRIM 16 silencing fragment was transfected into KYSE-270 cells. Transfection efficiency was determined using real-time quantitative polymerase chain reaction (qRT-PCR). Cell proliferation, invasiveness and migration were measured by 3-(4,5-dimethylthiazol2-yl)- 2,5-diphenyl tetrazolium bromide (MTT) assay, Transwell invasion assay, and scratch test, respectively. Protein expressions of bax and bcl-2 were assayed using Western blotting.Results: The gene expression of TRIM 16 was significantly upregulated in esophageal cancer cells, relative to normal human esophageal cells, but was downregulated after gene silencing. Moreover, the silencing of TRIM 16 gene led to significant reductions in KYSE-270 cell viability, migration and invasiveness, but significantly increased KYSE270 cell apoptosis (p < 0.05). The silencing of TRIM 16 gene also significantly upregulated bax protein expression, while downregulating the expression of bcl-2 protein (p < 0.05).Conclusion: These results suggest that TRIM 16 gene silencing inhibits KYSE-270 cell proliferation, invasion and metastasis, and thus provide a basis for its development as a therapeutic approach for the management of esophageal cancer. Keywords: Apoptosis, Cell invasion, Esophageal cancer, Gene silencing, Metastasis

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Jacques, David, Cy Jeffries, Matthew Caines, Michael Lammers, Donna Mallery, Amanda Price, Stephen McLaughlin, Chris Johnson, Dmitri Svergun, and Leo James. "TRIM protein domain topology and implications for antiviral immunity." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C243. http://dx.doi.org/10.1107/s2053273314097563.

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The tripartite motif (TRIM) proteins are a large family of >100 members, several of which have important roles in antiviral immunity and innate immune signaling. TRIM5α associates with incoming HIV-1 capsids, interfering with controlled disassembly and targeting them for degradation by the proteasome. TRIM21 is a cytosolic antibody receptor, which also targets incoming viral capsids for proteasomal degradation. TRIM25 is also involved in innate immunity, being essential for the ubiquitination of RIG-I. Recent positive selection analysis has predicted another 10 TRIM proteins with antiviral activity. Despite the fact that TRIM5α, 21 and 25 play key roles in antiviral protection, their mechanism of action is incompletely understood. All three proteins share a similar domain architecture, comprising a RING, B Box, coiled coil and PRYSPRY domains. The RING domains are responsible for ubiquitin ligase activity, while the PRYSPRY domains determine target specificity. We have used a combination of crystallography and SAXS to generate the first complete model for a TRIM protein structure. Crystallographic studies of TRIM25 reveal a central elongated coiled-coil domain with an unusual right-handed twist. The dimer formed by the coiled-coil is antiparallel but is followed by additional helices that reverse the direction of the protein chain. This structure suggests that the N-terminal domains of each monomer are separated but the C terminal domains are maintained in proximity. Multi-angle light scattering (MALS), isothermal titration calorimetry (ITC) and SAXS analysis confirms that this dimer structure is present in solution. Furthermore, scattering studies on the tripartite motif of TRIM21, comprising RING, B Box and coiled-coil, demonstrate that the first two domains of each monomer are held 150-200 Å apart. Finally, SAXS measurement of a complex between intact TRIM21 and its ligand, IgG Fc, provides the first empirical structure of a complete TRIM protein.

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Riddihough, Guy, and Stella M. Hurtley. "A protein to trim too-long telomeres." Science 355, no. 6325 (February 9, 2017): 591.9–592. http://dx.doi.org/10.1126/science.355.6325.591-i.

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Yondola, Mark A., and Patrick Hearing. "The Adenovirus E4 ORF3 Protein Binds and Reorganizes the TRIM Family Member Transcriptional Intermediary Factor 1 Alpha." Journal of Virology 81, no. 8 (February 7, 2007): 4264–71. http://dx.doi.org/10.1128/jvi.02629-06.

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ABSTRACT One of the most interesting functions attributed to the adenovirus early region 4 open reading frame 3 (E4 ORF3) protein is its reorganization of promyelocytic leukemia (PML) protein nuclear bodies. These normally punctate structures are reorganized by E4 ORF3 into tracks that eventually surround viral replication centers. PML rearrangement is an evolutionarily conserved function of E4 ORF3, yet its cause and functional relevance remain mysteries. The E4 ORF3 protein coimmunoprecipitates with the PML protein, yet E4 ORF3 still forms tracks in cells that lack PML. The PML protein is a member of a larger protein family termed tripartite motif (TRIM) proteins. TRIM proteins contain a tripartite domain structure in proximity to their N termini that consists of a RING finger domain, followed by one or two B box domains and a C-terminal coiled-coil domain (collectively termed the RBCC domain). The order and spacing of these domains are evolutionarily conserved and thought to mediate protein-protein interactions and other functions. We implemented a proteomic approach to isolate cellular proteins that bind to E4 ORF3. We identified a novel interaction between E4 ORF3 and another TRIM family member, transcriptional intermediary factor 1 alpha (TIF1α). TIF1α functions by recruiting coactivators and/or corepressors to modulate transcription. The interaction between E4 ORF3 and TIF1α was validated by coimmunoprecipitation and binding of recombinant proteins. Indirect immunofluorescence assays demonstrated that TIF1α is reorganized into track structures that contain PML upon E4 ORF3 expression. The RBCC domain of TIF1α is sufficient for E4 ORF3-induced rearrangement, and TIF1α reorganization is conserved across adenovirus serotypes.

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Fernandes, Alexandre P., Ana Águeda-Pinto, Ana Pinheiro, Hugo Rebelo, and Pedro J. Esteves. "Evolution of TRIM5 and TRIM22 in Bats Reveals a Complex Duplication Process." Viruses 14, no. 2 (February 8, 2022): 345. http://dx.doi.org/10.3390/v14020345.

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The innate immunological response in mammals involves a diverse and complex network of many proteins. Over the last years, the tripartite motif-containing protein 5 (TRIM5) and 22 (TRIM22) have shown promise as restriction factors of a plethora of viruses that infect primates. Although there have been studies describing the evolution of these proteins in a wide range of mammals, no prior studies of the TRIM6/34/5/22 gene cluster have been performed in the Chiroptera order. Here, we provide a detailed analysis of the evolution of this gene cluster in several bat genomes. Examination of different yangochiroptera and yinpterochiroptera bat species revealed a dynamic history of gene expansion occurring in TRIM5 and TRIM22 genes. Multiple copies of TRIM5 were found in the genomes of several bats, demonstrating a very low degree of conservation in the synteny of this gene among species of the Chiroptera order. Our findings also reveal that TRIM22 is often found duplicated in yangochiroptera bat species, an evolutionary phenomenon not yet observed in any other lineages of mammals. In total, we identified 31 TRIM5 and 19 TRIM22 amino acids to be evolving under positive selection, with most of the residues being placed in the PRYSPRY domain, known to be responsible for binding to the viral capsid during restriction in the primate orthologous TRIM proteins. Altogether, our results help to shed light on the distinctive role of bats in nature as reservoirs of viruses, many of which have become threatening zoonotic diseases through virus spillover in the last decades.

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Valletti, Marzano, Pesole, Sbisà, and Tullo. "Targeting Chemoresistant Tumors: Could TRIM Proteins-p53 Axis Be a Possible Answer?" International Journal of Molecular Sciences 20, no. 7 (April 10, 2019): 1776. http://dx.doi.org/10.3390/ijms20071776.

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Chemosensitivity is a crucial feature for all tumours so that they can be successfully treated, but the huge heterogeneity of these diseases, to be intended both inter- and intra-tumour, makes it a hard-to-win battle. Indeed, this genotypic and phenotypic variety, together with the adaptability of tumours, results in a plethora of chemoresistance acquisition mechanisms strongly affecting the effectiveness of treatments at different levels. Tripartite motif (TRIM) proteins are shown to be involved in some of these mechanisms thanks to their E3-ubiquitin ligase activity, but also to other activities they can exert in several cellular pathways. Undoubtedly, the ability to regulate the stability and activity of the p53 tumour suppressor protein, shared by many of the TRIMs, represents the preeminent link between this protein family and chemoresistance. Indeed, they can modulate p53 degradation, localization and subset of transactivated target genes, shifting the cellular response towards a cytoprotective or cytotoxic reaction to whatever damage induced by therapy, sometimes in a cellular-dependent way. The involvement in other chemoresistance acquisition mechanisms, independent by p53, is known, affecting pivotal processes like PI3K/Akt/NF-κB signalling transduction or Wnt/beta catenin pathway, to name a few. Hence, the inhibition or the enhancement of TRIM proteins functionality could be worth investigating to better understand chemoresistance and as a strategy to increase effectiveness of anticancer therapies.

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Salerno-Kochan, Anna, Andreas Horn, Pritha Ghosh, Chandran Nithin, Anna Kościelniak, Andreas Meindl, Daniela Strauss, et al. "Molecular insights into RNA recognition and gene regulation by the TRIM-NHL protein Mei-P26." Life Science Alliance 5, no. 8 (May 5, 2022): e202201418. http://dx.doi.org/10.26508/lsa.202201418.

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The TRIM-NHL protein Meiotic P26 (Mei-P26) acts as a regulator of cell fate in Drosophila. Its activity is critical for ovarian germline stem cell maintenance, differentiation of oocytes, and spermatogenesis. Mei-P26 functions as a post-transcriptional regulator of gene expression; however, the molecular details of how its NHL domain selectively recognizes and regulates its mRNA targets have remained elusive. Here, we present the crystal structure of the Mei-P26 NHL domain at 1.6 Å resolution and identify key amino acids that confer substrate specificity and distinguish Mei-P26 from closely related TRIM-NHL proteins. Furthermore, we identify mRNA targets of Mei-P26 in cultured Drosophila cells and show that Mei-P26 can act as either a repressor or activator of gene expression on different RNA targets. Our work reveals the molecular basis of RNA recognition by Mei-P26 and the fundamental functional differences between otherwise very similar TRIM-NHL proteins.

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Kirchgessner, Henning, Jes Dietrich, Jeanette Scherer, Pia Isomäki, Vladimir Korinek, Ivan Hilgert, Eddy Bruyns, Albrecht Leo, Andrew P. Cope, and Burkhart Schraven. "The Transmembrane Adaptor Protein Trim Regulates T Cell Receptor (Tcr) Expression and Tcr-Mediated Signaling via an Association with the Tcr ζ Chain." Journal of Experimental Medicine 193, no. 11 (June 4, 2001): 1269–84. http://dx.doi.org/10.1084/jem.193.11.1269.

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T cell receptor (TCR)-interacting molecule (TRIM) is a recently identified transmembrane adaptor protein, which is exclusively expressed in T cells. Here we demonstrate that in mature T cells, TRIM preferentially interacts with the TCR via the TCR-ζ chains and to a lesser extent via the CD3-ε/γ heterodimer. Transient or stable overexpression of TRIM in Jurkat T cells results in enhancement of TCR expression on the cell surface and elevated induction of Ca2+ mobilization after T cell activation. TRIM-mediated upregulation of TCR expression results from inhibition of spontaneous TCR internalization and stabilization of TCR complexes on the cell surface. Collectively, our data identify TRIM as a novel integral component of the TCR complex and suggest that one function of TRIM might be to modulate the strength of signals transduced through the TCR through regulation of TCR expression on the cell surface.

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D'Amico, Francesca, Rishov Mukhopadhyay, Huib Ovaa, and Monique P. C. Mulder. "Targeting TRIM Proteins: A Quest towards Drugging an Emerging Protein Class." ChemBioChem 22, no. 12 (March 18, 2021): 2011–31. http://dx.doi.org/10.1002/cbic.202000787.

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Guan, Xiaotao, Jun Li, Xingru Lü, Yu Dong, Weimin Chen, and Xuemei Li. "Expression, purification, crystallization and preliminary X-ray diffraction analysis of the C-terminal NHL domain of human TRIM2." Acta Crystallographica Section F Structural Biology Communications 70, no. 5 (April 25, 2014): 673–75. http://dx.doi.org/10.1107/s2053230x14008127.

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The tripartite motif-containing protein 2 (TRIM2) functions as an E3 ubiquitin ligase. Loss of function of TRIM2 has been shown to result in early-onset axonal neuropathy. As a member of the TRIM–NHL family of proteins, TRIM2 has a conserved modular architecture that includes N-terminal RING finger and B-box domains, a middle coiled-coil domain and a C-terminal NHL domain. To characterize the functional role of its NHL domain from the perspective of structural biology, a truncation of human TRIM2 (residues 465–744) was expressed, purified and crystallized. Rod-shaped crystals were obtained that diffracted X-rays to 1.7 Å resolution. The crystals belonged to space groupP21, with unit-cell parametersa= 43.6,b= 76.4,c= 107.4 Å, α = 90.0, β = 94.0, γ = 90.0°. A Matthews coefficient of 1.97 Å3 Da−1, corresponding to a solvent content of 37.6%, indicated the presence of three molecules per asymmetric unit, which was further confirmed by the phasing solution from molecular replacement.

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Jensen, Kirsten, Carol Shiels, and Paul S. Freemont. "PML protein isoforms and the RBCC/TRIM motif." Oncogene 20, no. 49 (October 2001): 7223–33. http://dx.doi.org/10.1038/sj.onc.1204765.

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Li, Chuanyou. "Gene Expression Profiling of TRIM Family in Individuals with Latent versus Active Tuberculosis and Reveals Potential Biomarkers for Diagnosis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 190.65. http://dx.doi.org/10.4049/jimmunol.202.supp.190.65.

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Abstract Tripartite motif (TRIM) protein family plays important regulatory roles in innate immune and inflammatory responses. Their dysregulation causes several diseases classified as virus infective diseases, cancers, immunological diseases, neuropsychiatric disorders, or developmental disorders. Nevertheless, the role and function of many members of TRIM family in tuberculosis (TB) remains largely unknown. Our study employed qRT-PCR to first profile the mRNA expression levels of 72 members of TRIM family in patients with active TB, latent tuberculosis infection (LTBI) and healthy individuals. Our results revealed a panel of TRIM genes markedly downregulated in patients with active TB when compared to LTBI subjects and healthy controls. Subsequently, in vitro cell infection experiment identified that some differentially expressed TRIM genes were specifically linked to Mtb infection. More importantly, we established the potential use of these dysregulated TRIM genes as biomarkers for the diagnosis of active TB from LTBI or healthy controls.

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Basu-Shrivastava, Meenakshi, Alina Kozoriz, Solange Desagher, and Iréna Lassot. "To Ubiquitinate or Not to Ubiquitinate: TRIM17 in Cell Life and Death." Cells 10, no. 5 (May 18, 2021): 1235. http://dx.doi.org/10.3390/cells10051235.

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TRIM17 is a member of the TRIM family, a large class of RING-containing E3 ubiquitin-ligases. It is expressed at low levels in adult tissues, except in testis and in some brain regions. However, it can be highly induced in stress conditions which makes it a putative stress sensor required for the triggering of key cellular responses. As most TRIM members, TRIM17 can act as an E3 ubiquitin-ligase and promote the degradation by the proteasome of substrates such as the antiapoptotic protein MCL1. Intriguingly, TRIM17 can also prevent the ubiquitination of other proteins and stabilize them, by binding to other TRIM proteins and inhibiting their E3 ubiquitin-ligase activity. This duality of action confers several pivotal roles to TRIM17 in crucial cellular processes such as apoptosis, autophagy or cell division, but also in pathological conditions as diverse as Parkinson’s disease or cancer. Here, in addition to recent data that endorse this duality, we review what is currently known from public databases and the literature about TRIM17 gene regulation and expression, TRIM17 protein structure and interactions, as well as its involvement in cell physiology and human disorders.

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Stoll, Guido A., Shun-ichiro Oda, Zheng-Shan Chong, Minmin Yu, Stephen H. McLaughlin, and Yorgo Modis. "Structure of KAP1 tripartite motif identifies molecular interfaces required for retroelement silencing." Proceedings of the National Academy of Sciences 116, no. 30 (July 9, 2019): 15042–51. http://dx.doi.org/10.1073/pnas.1901318116.

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Transcription of transposable elements is tightly regulated to prevent genome damage. KRAB domain-containing zinc finger proteins (KRAB-ZFPs) and KRAB-associated protein 1 (KAP1/TRIM28) play a key role in regulating retrotransposons. KRAB-ZFPs recognize specific retrotransposon sequences and recruit KAP1, inducing the assembly of an epigenetic silencing complex, with chromatin remodeling activities that repress transcription of the targeted retrotransposon and adjacent genes. Our biophysical and structural data show that the tripartite motif (TRIM) of KAP1 forms antiparallel dimers, which further assemble into tetramers and higher-order oligomers in a concentration-dependent manner. Structure-based mutations in the B-box 1 domain prevent higher-order oligomerization without significant loss of retrotransposon silencing activity, indicating that, in contrast to other TRIM-family proteins, self-assembly is not essential for KAP1 function. The crystal structure of the KAP1 TRIM dimer identifies the KRAB domain binding site in the coiled-coil domain near the dyad. Mutations at this site abolished KRAB binding and transcriptional silencing activity of KAP1. This work identifies the interaction interfaces in the KAP1 TRIM responsible for self-association and KRAB binding and establishes their role in retrotransposon silencing.

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Venuto, Santina, and Giuseppe Merla. "E3 Ubiquitin Ligase TRIM Proteins, Cell Cycle and Mitosis." Cells 8, no. 5 (May 27, 2019): 510. http://dx.doi.org/10.3390/cells8050510.

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The cell cycle is a series of events by which cellular components are accurately segregated into daughter cells, principally controlled by the oscillating activities of cyclin-dependent kinases (CDKs) and their co-activators. In eukaryotes, DNA replication is confined to a discrete synthesis phase while chromosome segregation occurs during mitosis. During mitosis, the chromosomes are pulled into each of the two daughter cells by the coordination of spindle microtubules, kinetochores, centromeres, and chromatin. These four functional units tie chromosomes to the microtubules, send signals to the cells when the attachment is completed and the division can proceed, and withstand the force generated by pulling the chromosomes to either daughter cell. Protein ubiquitination is a post-translational modification that plays a central role in cellular homeostasis. E3 ubiquitin ligases mediate the transfer of ubiquitin to substrate proteins determining their fate. One of the largest subfamilies of E3 ubiquitin ligases is the family of the tripartite motif (TRIM) proteins, whose dysregulation is associated with a variety of cellular processes and directly involved in human diseases and cancer. In this review we summarize the current knowledge and emerging concepts about TRIMs and their contribution to the correct regulation of cell cycle, describing how TRIMs control the cell cycle transition phases and their involvement in the different functional units of the mitotic process, along with implications in cancer progression.

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Jimenez-Moyano, Esther, Alba Ruiz, Henrik N. Kløverpris, Maria T. Rodriguez-Plata, Ruth Peña, Caroline Blondeau, David L. Selwood, et al. "Nonhuman TRIM5 Variants Enhance Recognition of HIV-1-Infected Cells by CD8+T Cells." Journal of Virology 90, no. 19 (July 20, 2016): 8552–62. http://dx.doi.org/10.1128/jvi.00819-16.

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ABSTRACTTripartite motif-containing protein 5 (TRIM5) restricts human immunodeficiency virus type 1 (HIV-1) in a species-specific manner by uncoating viral particles while activating early innate responses. Although the contribution of TRIM5 proteins to cellular immunity has not yet been studied, their interactions with the incoming viral capsid and the cellular proteasome led us to hypothesize a role for them. Here, we investigate whether the expression of two nonhuman TRIM5 orthologs, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), both of which are potent restrictors of HIV-1, could enhance immune recognition of infected cells by CD8+T cells. We illustrate how TRIM5 restriction improves CD8+T-cell-mediated HIV-1 inhibition. Moreover, when TRIM5 activity was blocked by the nonimmunosuppressive analog of cyclosporine (CsA), sarcosine-3(4-methylbenzoate)–CsA (SmBz-CsA), we found a significant reduction in CD107a/MIP-1β expression in HIV-1-specific CD8+T cells. This finding underscores the direct link between TRIM5 restriction and activation of CD8+T-cell responses. Interestingly, cells expressing RhT5 induced stronger CD8+T-cell responses through the specific recognition of the HIV-1 capsid by the immune system. The underlying mechanism of this process may involve TRIM5-specific capsid recruitment to cellular proteasomes and increase peptide availability for loading and presentation of HLA class I antigens. In summary, we identified a novel function for nonhuman TRIM5 variants in cellular immunity. We hypothesize that TRIM5 can couple innate viral sensing and CD8+T-cell activation to increase species barriers against retrovirus infection.IMPORTANCENew therapeutics to tackle HIV-1 infection should aim to combine rapid innate viral sensing and cellular immune recognition. Such strategies could prevent seeding of the viral reservoir and the immune damage that occurs during acute infection. The nonhuman TRIM5 variants, rhesus TRIM5α (RhT5) and TRIM-cyclophilin A (TCyp), are attractive candidates owing to their potency in sensing HIV-1 and blocking its activity. Here, we show that expression of RhT5 and TCyp in HIV-1-infected cells improves CD8+T-cell-mediated inhibition through the direct activation of HIV-1-specific CD8+T-cell responses. We found that the potency in CD8+activation was stronger for RhT5 variants and capsid-specific CD8+T cells in a mechanism that relies on TRIM5-dependent particle recruitment to cellular proteasomes. This novel mechanism couples innate viral sensing with cellular immunity in a single protein and could be exploited to develop innovative therapeutics for control of HIV-1 infection.

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Williams, Felix Preston, Kevin Haubrich, Cecilia Perez-Borrajero, and Janosch Hennig. "Emerging RNA-binding roles in the TRIM family of ubiquitin ligases." Biological Chemistry 400, no. 11 (November 26, 2019): 1443–64. http://dx.doi.org/10.1515/hsz-2019-0158.

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Abstract TRIM proteins constitute a large, diverse and ancient protein family which play a key role in processes including cellular differentiation, autophagy, apoptosis, DNA repair, and tumour suppression. Mostly known and studied through the lens of their ubiquitination activity as E3 ligases, it has recently emerged that many of these proteins are involved in direct RNA binding through their NHL or PRY/SPRY domains. We summarise the current knowledge concerning the mechanism of RNA binding by TRIM proteins and its biological role. We discuss how RNA-binding relates to their previously described functions such as E3 ubiquitin ligase activity, and we will consider the potential role of enrichment in membrane-less organelles.

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Kar, Alak Kanti, Felipe Diaz-Griffero, Yuan Li, Xing Li, and Joseph Sodroski. "Biochemical and Biophysical Characterization of a Chimeric TRIM21-TRIM5α Protein." Journal of Virology 82, no. 23 (September 17, 2008): 11669–81. http://dx.doi.org/10.1128/jvi.01559-08.

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ABSTRACT The tripartite motif (TRIM) protein, TRIM5α, is an endogenous factor in primates that recognizes the capsids of certain retroviruses after virus entry into the host cell. TRIM5α promotes premature uncoating of the capsid, thus blocking virus infection. Low levels of expression and tendencies to aggregate have hindered the biochemical, biophysical, and structural characterization of TRIM proteins. Here, a chimeric TRIM5α protein (TRIM5Rh-21R) with a RING domain derived from TRIM21 was expressed in baculovirus-infected insect cells and purified. Although a fraction of the TRIM5Rh-21R protein formed large aggregates, soluble fractions of the protein formed oligomers (mainly dimers), exhibited a protease-resistant core, and contained a high percentage of helical secondary structure. Cross-linking followed by negative staining and electron microscopy suggested a globular structure. The purified TRIM5Rh-21R protein displayed E3-ligase activity in vitro and also self-ubiquitylated in the presence of ubiquitin-activating and -conjugating enzymes. The purified TRIM5Rh-21R protein specifically associated with human immunodeficiency virus type 1 capsid-like complexes; a deletion within the V1 variable region of the B30.2(SPRY) domain decreased capsid binding. Thus, the TRIM5Rh-21R restriction factor can directly recognize retroviral capsid-like complexes in the absence of other mammalian proteins.

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Kölsch, Uwe, Börge Arndt, Dirk Reinhold, Jonathan A. Lindquist, Nicole Jüling, Stefanie Kliche, Klaus Pfeffer, Eddy Bruyns, Burkhart Schraven, and Luca Simeoni. "Normal T-Cell Development and Immune Functions in TRIM-Deficient Mice." Molecular and Cellular Biology 26, no. 9 (May 1, 2006): 3639–48. http://dx.doi.org/10.1128/mcb.26.9.3639-3648.2006.

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ABSTRACT The transmembrane adaptor molecule TRIM is strongly expressed within thymus and in peripheral CD4+ T cells. Previous studies suggested that TRIM is an integral component of the T-cell receptor (TCR)/CD3 complex and might be involved in regulating TCR cycling. To elucidate the in vivo function of TRIM, we generated TRIM-deficient mice by homologous recombination. TRIM−/− mice develop normally and are healthy and fertile. However, the animals show a mild reduction in body weight that appears to be due to a decrease in the size and/or cellularity of many organs. The morphology and anatomy of nonlymphoid as well as primary and secondary lymphoid organs is normal. The frequency of thymocyte and peripheral T-cell subsets does not differ from control littermates. In addition, a detailed analysis of lymphocyte development revealed that TRIM is not required for either positive or negative selection. Although TRIM−/− CD4+ T cells showed an augmented phosphorylation of the serine/threonine kinase Akt, the in vitro characterization of peripheral T cells indicated that proliferation, survival, activation-induced cell death, migration, adhesion, TCR internalization and recycling, TCR-mediated calcium fluxes, tyrosine phosphorylation, and mitogen-activated protein family kinase activation are not affected in the absence of TRIM. Similarly, the in vivo immune response to T-dependent and T-independent antigens as well as the clinical course of experimental autoimmune encephalomyelitis, a complex Th1-mediated autoimmune model, is comparable to that of wild-type animals. Collectively, these results demonstrate that TRIM is dispensable for T-cell development and peripheral immune functions. The lack of an evident phenotype could indicate that TRIM shares redundant functions with other transmembrane adaptors involved in regulating the immune response.

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Ylinen, Laura M. J., Zuzana Keckesova, Benjamin L. J. Webb, Robert J. M. Gifford, Timothy P. L. Smith, and Greg J. Towers. "Isolation of an Active Lv1 Gene from Cattle Indicates that Tripartite Motif Protein-Mediated Innate Immunity to Retroviral Infection Is Widespread among Mammals." Journal of Virology 80, no. 15 (August 1, 2006): 7332–38. http://dx.doi.org/10.1128/jvi.00516-06.

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ABSTRACT Lv1/TRIM5α (tripartite motif 5α) has recently emerged as an important factor influencing species-specific permissivity to retroviral infection in a range of primates, including humans. Old World monkey TRIM5α blocks human immunodeficiency virus type 1 (HIV-1) infectivity, and the human and New World monkey TRIM5α proteins are inactive against HIV-1 but active against divergent murine (N-tropic murine leukemia virus [MLV-N]) and simian (simian immunodeficiency virus from rhesus macaque [SIVmac]) retroviruses, respectively. Here we demonstrate antiviral activity of the first nonprimate TRIM protein, from cattle, active against divergent retroviruses, including HIV-1. The number of closely related human TRIM sequences makes assignment of the bovine sequence as a TRIM5α ortholog uncertain, and we therefore refer to it as bovine Lv1. Bovine Lv1 is closely related to primate TRIM5α proteins in the N-terminal RING and B-box 2 domains but significantly less homologous in the C-terminal B30.2 domain, particularly in the region shown to influence antiviral specificity. Intriguingly, some viruses restricted by bovine Lv1, including HIV-1 and MLV-N, are unable to synthesize viral DNA by reverse transcription, whereas restricted HIV-2 makes normal amounts of DNA. The data support the conclusion that TRIM protein-mediated restriction of retroviral infection is a more common attribute of mammals than previously appreciated.

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Allouch, Awatef, Cristina Di Primio, Emanuele Alpi, Marina Lusic, Daniele Arosio, Mauro Giacca, and Anna Cereseto. "The TRIM Family Protein KAP1 Inhibits HIV-1 Integration." Cell Host & Microbe 9, no. 6 (June 2011): 484–95. http://dx.doi.org/10.1016/j.chom.2011.05.004.

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Keown, Jeremy R., Joy Yang, Moyra M. Black, and David C. Goldstone. "The RING domain of TRIM69 promotes higher-order assembly." Acta Crystallographica Section D Structural Biology 76, no. 10 (September 16, 2020): 954–61. http://dx.doi.org/10.1107/s2059798320010499.

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Members of the TRIM protein family have been shown to inhibit a range of viral infections. Recently, TRIM69 was identified as a potent inhibitor of Vesicular stomatitis Indiana virus infection, with its inhibition being dependent upon multimerization. Using SEC-MALLS analysis, it is demonstrated that the assembly of TRIM69 is mediated through the RING domain and not the Bbox domain as has been shown for other TRIM proteins. Using X-ray crystallography, the structure of the TRIM69 RING domain has been determined to a resolution of 2.1 Å, the oligomerization interface has been identified and regions outside the four-helix bundle have been observed to form interactions that are likely to support assembly.

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O'Connor, Christopher, Thomas Pertel, Seth Gray, Seth L. Robia, Joanna C. Bakowska, Jeremy Luban, and Edward M. Campbell. "p62/Sequestosome-1 Associates with and Sustains the Expression of Retroviral Restriction Factor TRIM5α." Journal of Virology 84, no. 12 (March 31, 2010): 5997–6006. http://dx.doi.org/10.1128/jvi.02412-09.

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ABSTRACT TRIM5 proteins mediate a potent block to the cross-species transmission of retroviruses, the most well known being the TRIM5α protein from rhesus macaques, which potently inhibits human immunodeficiency virus type 1 (HIV-1) infection. This restriction occurs at an early stage in the replication cycle and is mediated by the binding of TRIM5 proteins to determinants present in the retroviral capsid. TRIM5α, as well as other TRIM family proteins, has been shown to be regulated by interferons (IFN). Here we show that TRIM5α associates with another IFN-induced gene, sequestosome-1/p62 (p62). p62 plays a role in several signal transduction cascades that are important for maintaining the antiviral state of cells. Here we demonstrate that p62 localizes to both human and rhesus macaque TRIM5α cytoplasmic bodies, and fluorescence resonance energy transfer (FRET) analysis demonstrates that these proteins closely associate in these structures. When p62 expression was knocked down via small interfering RNA (siRNA), the number of TRIM5α cytoplasmic bodies and the level of TRIM5α protein expression were reduced in cell lines stably expressing epitope-tagged versions of TRIM5α. In accordance with these data, p62 knockdown resulted in reduced TRIM5α-mediated retroviral restriction in cells expressing epitope-tagged TRIM5α or expressing endogenously expressed human TRIM5α. p62 may therefore operate to enhance TRIM5α-mediated retroviral restriction, contributing to the antiviral state of cells following IFN treatment.

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Tozawa, Takafumi, Kohichi Matsunaga, Tetsuro Izumi, Naotake Shigehisa, Takamasa Uekita, Masato Taoka, and Tohru Ichimura. "Ubiquitination-coupled liquid phase separation regulates the accumulation of the TRIM family of ubiquitin ligases into cytoplasmic bodies." PLOS ONE 17, no. 8 (August 5, 2022): e0272700. http://dx.doi.org/10.1371/journal.pone.0272700.

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Many members of the tripartite motif (TRIM) family of ubiquitin ligases localize in spherical, membrane-free structures collectively referred to as cytoplasmic bodies (CBs) in a concentration-dependent manner. These CBs may function as aggresome precursors or storage compartments that segregate potentially harmful excess TRIM molecules from the cytosolic milieu. However, the manner in which TRIM proteins accumulate into CBs is unclear. In the present study, using TRIM32, TRIM5α and TRIM63 as examples, we demonstrated that CBs are in a liquid droplet state, resulting from liquid-liquid phase separation (LLPS). This finding is based on criteria that defines phase-separated structures, such as recovery after photobleaching, sensitivity to hexanediol, and the ability to undergo fusion. CB droplets, which contain cyan fluorescent protein (CFP)-fused TRIM32, were purified from HEK293 cells using a fluorescence-activated cell sorter and analyzed by LC-MS/MS. We found that in addition to TRIM32, these droplets contain a variety of endogenous proteins and enzymes including ubiquitin. Localization of ubiquitin within CBs was further verified by fluorescence microscopy. We also found that the activation of the intracellular ubiquitination cascade promotes the assembly of TRIM32 molecules into CBs, whereas inhibition causes suppression. Regulation is dependent on the intrinsic E3 ligase activity of TRIM32. Similar regulation by ubiquitination on the TRIM assembly was also observed with TRIM5α and TRIM63. Our findings provide a novel mechanical basis for the organization of CBs that couples compartmentalization through LLPS with ubiquitination.

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Guo, Mengmeng, Wenyan Cao, Shengwen Chen, Renyun Tian, Binbin Xue, Luoling Wang, Qian Liu, et al. "TRIM21 Regulates Virus-Induced Cell Pyroptosis through Polyubiquitination of ISG12a." Journal of Immunology 209, no. 10 (November 15, 2022): 1987–98. http://dx.doi.org/10.4049/jimmunol.2200163.

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Abstract Pyroptosis is a form of regulated cell death mediated by the gasdermin protein family. During virus infection, cell pyroptosis restricts viral replication. The mechanisms of the tripartite motif (TRIM) protein family and IFN-stimulated genes (ISGs) against viruses have been studied. The role of TRIMs and ISGs in pyroptosis remains unclear. In this study, we show that TRIM21 interacts with ISG12a in viral infection and facilitates its translocation into the mitochondria by promoting its ubiquitination, thereby causing caspase 3 activation. Gasdermin E (GSDME) is specifically cleaved by caspase 3 upon viral infection, releasing the GSDME N-terminal domain, perforating the cell membrane, and causing cell pyroptosis. Our study uncovers a new mechanism of TRIM21 and ISG12a in regulating virus-induced cell pyroptosis.

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Pagani, Isabel, Guido Poli, and Elisa Vicenzi. "TRIM22. A Multitasking Antiviral Factor." Cells 10, no. 8 (July 23, 2021): 1864. http://dx.doi.org/10.3390/cells10081864.

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Viral invasion of target cells triggers an immediate intracellular host defense system aimed at preventing further propagation of the virus. Viral genomes or early products of viral replication are sensed by a number of pattern recognition receptors, leading to the synthesis and production of type I interferons (IFNs) that, in turn, activate a cascade of IFN-stimulated genes (ISGs) with antiviral functions. Among these, several members of the tripartite motif (TRIM) family are antiviral executors. This article will focus, in particular, on TRIM22 as an example of a multitarget antiviral member of the TRIM family. The antiviral activities of TRIM22 against different DNA and RNA viruses, particularly human immunodeficiency virus type 1 (HIV-1) and influenza A virus (IAV), will be discussed. TRIM22 restriction of virus replication can involve either direct interaction of TRIM22 E3 ubiquitin ligase activity with viral proteins, or indirect protein–protein interactions resulting in control of viral gene transcription, but also epigenetic effects exerted at the chromatin level.

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Alexeev, Andrey, Tatyana Alexeeva, Larisa Enaleva, Tatyana Tupolskikh, and Nataliia Shumskaia. "Prospects for the use of protein-carbohydrate complex based on mung bean seeds in the functional meat products technology." E3S Web of Conferences 175 (2020): 08004. http://dx.doi.org/10.1051/e3sconf/202017508004.

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The use of new non-traditional types of plant materials in the diet is one of the ways to improve the meat products’ quality. The combination of plant proteins with animals creates biologically active amino-acid complexes which increase its bioavailability for organism and biological value of the product. In this case, the use of non-traditional plant materials in the production technology of new types of sausage products to improve the quality of the end product is prospective and relevant. Research objective is development of formulations and technologies for new types of high biological value products, based on combination of meat raw materials with functional additives of plant origin. The work was performed at the Department of Food Technology FSBEI HE «Don State Agrarian University», Persianovsky, Rostov region. The objects of research were the new protein-carbohydrate complexes based on flour from germinated seeds of mung bean, control and model forcemeat based on trim beef of first grade, lean trim pork and mid fat trim pork, and end products. Introduction to the cooked sausage products formulation of mung bean germinated seeds flour has a beneficial effect on the organoleptic properties of the end product and enriches it with biologically valuable substances.

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Dang, Xiaoyan, Yong Qin, Changwei Gu, Jiangli Sun, Rui Zhang, and Zhuo Peng. "Knockdown of Tripartite Motif 8 Protects H9C2 Cells Against Hypoxia/Reoxygenation-Induced Injury Through the Activation of PI3K/Akt Signaling Pathway." Cell Transplantation 29 (January 1, 2020): 096368972094924. http://dx.doi.org/10.1177/0963689720949247.

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Tripartite motif 8 (TRIM8) is a member of the TRIM protein family that has been found to be implicated in cardiovascular disease. However, the role of TRIM8 in myocardial ischemia/reperfusion (I/R) has not been investigated. We aimed to explore the effect of TRIM8 on cardiomyocyte H9c2 cells exposed to hypoxia/reoxygenation (H/R). We found that TRIM8 expression was markedly upregulated in H9c2 cells after stimulation with H/R. Gain- and loss-of-function assays proved that TRIM8 knockdown improved cell viability of H/R-stimulated H9c2 cells. In addition, TRIM8 knockdown suppressed reactive oxygen species production and elevated the levels of superoxide dismutase and glutathione peroxidase. Knockdown of TRIM8 suppressed the caspase-3 activity, as well as caused significant increase in bcl-2 expression and decrease in bax expression. Furthermore, TRIM8 overexpression exhibited apposite effects with knockdown of TRIM8. Finally, knockdown of TRIM8 enhanced the activation of PI3K/Akt signaling pathway in H/R-stimulated H9c2 cells. Inhibition of PI3K/Akt by LY294002 reversed the effects of TRIM8 knockdown on cell viability, oxidative stress, and apoptosis of H9c2 cells. These present findings defined TRIM8 as a therapeutic target for attenuating and preventing myocardial I/R injury.

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James, L. C., A. H. Keeble, Z. Khan, D. A. Rhodes, and J. Trowsdale. "Structural basis for PRYSPRY-mediated tripartite motif (TRIM) protein function." Proceedings of the National Academy of Sciences 104, no. 15 (March 30, 2007): 6200–6205. http://dx.doi.org/10.1073/pnas.0609174104.

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Mevissen, Tycho E. T., Anisa V. Prasad, and Johannes C. Walter. "TRIM21-dependent target protein ubiquitination mediates cell-free Trim-Away." Cell Reports 42, no. 2 (February 2023): 112125. http://dx.doi.org/10.1016/j.celrep.2023.112125.

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Rajsbaum, Ricardo, Gijs Versteeg, Sonja Schmid, Ana Maestre, Alan Belicha-Villanueva, Ana Fernandez-Sesma, Benjamin tenOever, and Adolfo García-Sastre. "Unanchored Lysine48-linked polyubiquitin chains positively regulate the type I IFN-mediated antiviral response (P1391)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 57.7. http://dx.doi.org/10.4049/jimmunol.190.supp.57.7.

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Abstract Type-I interferons (IFN-I) are essential antiviral cytokines produced upon microbial infection. IFN-I elicits this activity through the upregulation of 100s of IFN-I stimulated genes (ISGs), many of which have known antiviral activity. The full breadth of ISG induction requires activation of a number of cellular factors including the IκB kinase epsilon (IKKϵ). However, the mechanism of IKKϵ activation upon viral infection or IFN receptor signaling remains elusive. Here we show that TRIM6, a member of the E3-ubiquitin ligase tripartite motif (TRIM) family of proteins, interacts with IKKϵ and promotes induction of IKKϵ-dependent ISGs. Some studies have suggested a role for unanchored K63-linked polyubiquitin chains, which are not conjugated to any protein, in regulation of kinase activity. However, no role has yet been established for unanchored K48-linked polyubiquitin chains in kinase activation. We show that TRIM6 and the E2-ubiquitin conjugase UbE2K cooperate in the synthesis of unanchored K48-linked polyubiquitin chains, which activate IKKϵ for subsequent STAT1 phosphorylation. Our work defines a previously unrecognized activating role of K48-linked unanchored polyubiquitin chains in kinase activation and identifies the UbE2K-TRIM6-ubiquitin axis as critical for IFN signaling and antiviral response.

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Rybakowska, Paulina, Nina Wolska, Arkadiusz Klopocki, Kathy Sivils, Judith James, Harini Bagavant, and Umesh Deshmukh. "Multiple TRIM proteins are targets of autoimmune response in lupus and Sjogren's syndrome. (HUM7P.308)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 184.17. http://dx.doi.org/10.4049/jimmunol.192.supp.184.17.

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Abstract TRIM21 belongs to the large family of tripartite motif containing proteins, and is often targeted by autoantibodies in lupus and Sjogren’s syndrome. Considering the significant protein domain homology between different TRIM proteins, we hypothesized that additional TRIM proteins are targets of autoimmunity. Based on the literature, in this study we investigated autoantibody responses to TRIM38. While 9% of lupus patients (n=149) had anti-TRIM38 antibodies, the incidence in Sjogren’s syndrome patients (n=150) was 12%, and in controls (n=50) it was 4%. With respect to TRIM21, the incidence was 62%, 68%, and 4% respectively. In Sjogren’s syndrome patients, the presence of anti-TRIM38 antibodies was closely associated with the increased severity of dry eye parameters. Epitope mapping studies showed that anti-TRIM21 antibodies reacted with the RING, Coiled coil and PRY-SPRY domains of TRIM21, whereas anti-TRIM38 antibodies reacted only with the Coiled coil and PRY-SPRY domains of TRIM38. All anti-TRIM38 positive patients also had anti-TRIM21 antibodies. Affinity purified anti-TRIM21 antibodies from lupus patients did not immunoprecipitate TRIM38, indicating lack of cross-reactivity at B cell level. However, we observed T cell cross-reactivity between TRIM21298-312 and TRIM38302-316. Our study suggests that immune responses to TRIM proteins can evolve through epitope spreading and contribute towards exacerbating the pathogenesis in autoimmune disorders.

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Kim, Ae, Isamu Hartman, and Scheherazade Sadegh-Nasseri. "Survival of antigenic epitope requires class II MHC capture prior to lysosomal proteolysis (93.21)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S170. http://dx.doi.org/10.4049/jimmunol.178.supp.93.21.

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Abstract The paradigmatic model for the generation of peptide determinants for class II major histocompatibility complex molecules (MHC II) is that proteolytic fragmentation of antigen precedes the capture of the resulting peptides by MHC II (cut/trim first, bind later). However, circumstantial evidence exists to support an alternate model in which MHC II binding of antigenic epitope occurs prior to the proteolytic fragmentation of that antigen (bind first, cut/trim later). To distinguish between these two models, we analyzed the interaction of HLA-DR1 with two protein antigens, type II collagen and influenza hemagglutinin. Here, using a novel cell?free antigen processing system composed solely of purified soluble protein components, HLA-DR1, two cathepsins, and HLA-DM, combined with mass spectrometric identification of the bound peptides, we demonstrate for both antigens that; the protein antigens bind MHC class II prior to digestion by lysosomal proteases,the immunodominant epitope of the antigens are degraded by lysosomal proteases if not bound to MHC class II, andthe epitopes, when bound to MHCII, are protected from proteolytic degradation. These findings conclusively support the “bind first, cut/trim later” model and have important implications in understanding the sequence of events in antigen processing and the correlation between antigen structure and immunodominance.

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Sellman, Jeff E., Keith C. DeRuisseau, Jenna L. Betters, Vitor A. Lira, Quinlyn A. Soltow, Joshua T. Selsby, and David S. Criswell. "In vivo inhibition of nitric oxide synthase impairs upregulation of contractile protein mRNA in overloaded plantaris muscle." Journal of Applied Physiology 100, no. 1 (January 2006): 258–65. http://dx.doi.org/10.1152/japplphysiol.00936.2005.

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Inhibition of nitric oxide synthase (NOS) activity in vivo impedes hypertrophy in the overloaded rat plantaris. We investigated the mechanism for this effect by examining early events leading to muscle growth following 5 or 12 days of functional overload. Male Sprague-Dawley rats (∼350 g) were randomly divided into three treatment groups: control, NG-nitro-l-arginine methyl ester (l-NAME; 90 mg·kg−1·day−1), and 1-(2-trifluoromethyl-phenyl)-imidazole (TRIM; 10 mg·kg−1·day−1). Unilateral removal of synergists induced chronic overload (OL) of the right plantaris. Sham surgery performed on the left hindlimb served as a normally loaded control. l-NAME and TRIM treatments prevented OL-induced skeletal α-actin and type I (slow) myosin heavy chain mRNA expression at 5 days. Conversely, neither l-NAME nor TRIM affected hepatocyte growth factor or VEGF mRNA responses to OL at 5 days. However, OL induction of IGF-I and mechanogrowth factor mRNA was greater ( P < 0.05) in the TRIM group compared with the controls. Furthermore, the phosphorylated-to-total p70 S6 kinase ratio was higher in OL muscle from NOS-inhibited groups, compared with control OL. At 12 days of OL, the cumulative proliferation of plantaris satellite cells was assessed by subcutaneous implantation of time release 5′-bromo-2′-deoxyuridine pellets during the OL-inducing surgeries. Although OL caused a fivefold increase in the number of mitotically active (5′-bromo-2′-deoxyuridine positive) sublaminar nuclei, this was unaffected by concurrent NOS inhibition. Therefore, NOS activity may provide negative feedback control of IGF-I/p70 S6 kinase signaling during muscle growth. Moreover, NOS activity may be involved in transcriptional regulation of skeletal α-actin and type I (slow) myosin heavy chain during functional overload.

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Li, Xue, Lin Yang, Si Chen, Jiawei Zheng, Huimin Zhang, and Linzhu Ren. "Multiple Roles of TRIM21 in Virus Infection." International Journal of Molecular Sciences 24, no. 2 (January 14, 2023): 1683. http://dx.doi.org/10.3390/ijms24021683.

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The tripartite motif protein 21 (TRIM21) belongs to the TRIM family, possessing an E3 ubiquitin ligase activity. Similar to other TRIMs, TRIM21 also contains three domains (named RBCC), including the Really Interesting New Gene (RING) domain, one or two B-Box domains (B-Box), and one PRY/SPRY domain. Notably, we found that the RING and B-Box domains are relatively more conservative than the PRY/SPRY domain, suggesting that TRIM21 of different species had similar functions. Recent results showed that TRIM21 participates in virus infection by directly interacting with viral proteins or modulating immune and inflammatory responses. TRIM21 also acts as a cytosol high-affinity antibody Fc receptor, binding to the antibody–virus complex and triggering an indirect antiviral antibody-dependent intracellular neutralization (ADIN). This paper focuses on the recent progress in the mechanism of TRIM21 during virus infection and the application prospects of TRIM21 on virus infection.

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Journal articles on the topic 'TRIM protein'

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