Abstract 218: The Role of Novel Tripartite Motif Proteins in Sarcolemmal Membrane Repair

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Liubov V Gushchina ◽  
Jenna Alloush ◽  
Sayak Bhattacharya ◽  
Zhaobin Xu ◽  
Eric X Beck ◽  
...  
Keyword(s):  
Membrane Damage ◽  
Coiled Coil ◽  
Cardiac Cells ◽  
Acute Injury ◽  
Membrane Repair ◽  
Repair Capacity ◽  
E3 Ligases ◽  
Tripartite Motif ◽  
Trim Proteins

Tripartite motif (TRIM) proteins are a superfamily of coiled-coil-containing RING E3 ligases that function in many cellular processes, particularly in membrane repair pathways. Mitsugumin 53 (MG53) also known as TRIM72, is primary expressed in skeletal muscle and heart. Our experimental data confirm that during membrane damage, MG53 translocates to the injury site and acts as a molecular glue to reseal the damage area. The role of MG53 in membrane repair has been demonstrated in both in vitro studies using molecular approaches and in vivo using rodent wild type and knockout models. Thus, our data indicate that recombinant human MG53 protein can be directly applied as a therapeutic agent to increase the membrane repair capacity of many cell types, including cardiomyocytes during acute injury or in chronic disease progression. However, the precise mechanism and potential partners by which MG53 executes its membrane repair function are not completely understood. On the basis of the global TRIM family protein alignment, we hypothesize that there are other TRIM proteins that, alone or together with MG53, may facilitate repair by targeting the site of an injury. Moreover, data from our lab demonstrated that MG53 and these TRIM proteins can form homo- and hetero-oligomeric assemblies due to the presence of the coiled-coil region in these proteins and, further, that this may be necessary for the active membrane resealing process. Using E. coli protein expression methodology we can generate and isolate new TRIM recombinant proteins and test if these protein complexes are effective when applied externally to cardiac and non-cardiac cells. These novel proteins will also be tested for their pharmacokinetic properties to determine their efficacy in both acute and chronic applications. Our studies should increase our knowledge of the mechanisms controlling cardiac membrane repair and also provide novel therapeutic targets.

scholarly journals TRIM Proteins and Their Roles in Antiviral Host Defenses

2018 ◽  
Vol 5 (1) ◽  
pp. 385-405 ◽  
Author(s):  
Michiel van Gent ◽  
Konstantin M.J. Sparrer ◽  
Michaela U. Gack
Keyword(s):  
Host Defense ◽  
Host Immunity ◽  
Innate Immune ◽  
Host Defenses ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Cytokine Responses ◽  
Tripartite Motif ◽  
Trim Proteins

Tripartite motif (TRIM) proteins are a versatile family of ubiquitin E3 ligases involved in a multitude of cellular processes. Studies in recent years have demonstrated that many TRIM proteins play central roles in the host defense against viral infection. While some TRIM proteins directly antagonize distinct steps in the viral life cycle, others regulate signal transduction pathways induced by innate immune sensors, thereby modulating antiviral cytokine responses. Furthermore, TRIM proteins have been implicated in virus-induced autophagy and autophagy-mediated viral clearance. Given the important role of TRIM proteins in antiviral restriction, it is not surprising that several viruses have evolved effective maneuvers to neutralize the antiviral action of specific TRIM proteins. Here, we describe the major antiviral mechanisms of TRIM proteins as well as viral strategies to escape TRIM-mediated host immunity.

Functional interactions between ubiquitin E2 enzymes and TRIM proteins

2011 ◽  
Vol 434 (2) ◽  
pp. 309-319 ◽  
Author(s):  
Luisa M. Napolitano ◽  
Ellis G. Jaffray ◽  
Ronald T. Hay ◽  
Germana Meroni
Keyword(s):  
Coiled Coil ◽  
Specific Interactions ◽  
E3 Ligases ◽  
Cellular Processes ◽  
Coiled Coil Region ◽  
Physiological Relevance ◽  
Tripartite Motif ◽  
E2 Enzymes ◽  
Specific Reactions ◽  
Trim Proteins

The TRIM (tripartite motif) family of proteins is characterized by the presence of the tripartite motif module, composed of a RING domain, one or two B-box domains and a coiled-coil region. TRIM proteins are involved in many cellular processes and represent the largest subfamily of RING-containing putative ubiquitin E3 ligases. Whereas their role as E3 ubiquitin ligases has been presumed, and in several cases established, little is known about their specific interactions with the ubiquitin-conjugating E2 enzymes or UBE2s. In the present paper, we report a thorough screening of interactions between the TRIM and UBE2 families. We found a general preference of the TRIM proteins for the D and E classes of UBE2 enzymes, but we also revealed very specific interactions between TRIM9 and UBE2G2, and TRIM32 and UBE2V1/2. Furthermore, we demonstrated that the TRIM E3 activity is only manifest with the UBE2 with which they interact. For most specific interactions, we could also observe subcellular co-localization of the TRIM involved and its cognate UBE2 enzyme, suggesting that the specific selection of TRIM–UBE2 pairs has physiological relevance. Our findings represent the basis for future studies on the specific reactions catalysed by the TRIM E3 ligases to determine the fate of their targets.

scholarly journals Emerging RNA-binding roles in the TRIM family of ubiquitin ligases

2019 ◽  
Vol 400 (11) ◽  
pp. 1443-1464 ◽  
Author(s):  
Felix Preston Williams ◽  
Kevin Haubrich ◽  
Cecilia Perez-Borrajero ◽  
Janosch Hennig
Keyword(s):  
Ubiquitin Ligase ◽  
Cellular Differentiation ◽  
Potential Role ◽  
Rna Binding ◽  
Current Knowledge ◽  
E3 Ligases ◽  
Tumour Suppression ◽  
Ubiquitin Ligase Activity ◽  
Trim Proteins

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.

scholarly journals Functional Replacement of the RING, B-Box 2, and Coiled-Coil Domains of Tripartite Motif 5α (TRIM5α) by Heterologous TRIM Domains

2006 ◽  
Vol 80 (13) ◽  
pp. 6198-6206 ◽  
Author(s):  
Xing Li ◽  
Yuan Li ◽  
Matthew Stremlau ◽  
Wen Yuan ◽  
Byeongwoon Song ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Coiled Coil ◽  
Chimeric Proteins ◽  
Immunodeficiency Virus ◽  
Tripartite Motif ◽  
Trim Proteins ◽  
Hiv 1 ◽  
Functional Replacement ◽  
Distant Relative

ABSTRACT Tripartite motif 5α (TRIM5α) restricts some retroviruses, including human immunodeficiency virus type 1 (HIV-1), from infecting the cells of particular species. TRIM5α is a member of the TRIM family of proteins, which contain RING, B-box, coiled-coil (CC), and, in some cases, B30.2(SPRY) domains. Here we investigated the abilities of domains from TRIM proteins (TRIM6, TRIM34, and TRIM21) that do not restrict HIV-1 infection to substitute for the domains of rhesus monkey TRIM5α (TRIM5αrh). The RING, B-box 2, and CC domains of the paralogous TRIM6 and TRIM34 proteins functionally replaced the corresponding TRIM5αrh domains, allowing HIV-1 restriction. By contrast, similar chimeras containing the components of TRIM21, a slightly more distant relative of TRIM5, did not restrict HIV-1 infection. The TRIM21 B-box 2 domain and its flanking linker regions contributed to the functional defectiveness of these chimeras. All of the chimeric proteins formed trimers. All of the chimeras that restricted HIV-1 infection bound the assembled HIV-1 capsid complexes. These results indicate that heterologous RING, B-box 2, and CC domains from related TRIM proteins can functionally substitute for TRIM5αrh domains.

scholarly journals Structural analysis of RIG-I-like receptors reveals ancient rules of engagement between diverse RNA helicases and TRIM ubiquitin ligases

2020 ◽  
Author(s):  
Kazuki Kato ◽  
Sadeem Ahmad ◽  
Zixiang Zhu ◽  
Janet M. Young ◽  
Xin Mu ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Rna Helicases ◽  
Animal Evolution ◽  
E3 Ligases ◽  
Cryo Electron Microscopy ◽  
Rna Biology ◽  
Evolutionarily Conserved ◽  
Tripartite Motif ◽  
Biochemical Analyses ◽  
Trim Proteins

AbstractRNA helicases and ubiquitin E3 ligases mediate many critical functions within cells, but their actions have been studied largely in distinct biological contexts. Here, we uncover evolutionarily conserved rules of engagement between RNA helicases and tripartite motif (TRIM) E3 ligases that lead to their functional coordination in vertebrate innate immunity. Using cryo-electron microscopy and biochemistry, we show that RIG-I-like receptors (RLRs), viral RNA receptors with helicase domains, interact with their cognate TRIM/TRIM-like E3 ligases through similar epitopes in the helicase domains. Their interactions are avidity-driven, restricting the actions of TRIM/TRIM-like proteins and consequent immune activation to RLR multimers. Mass-spectrometry and phylogeny-guided biochemical analyses further reveal that similar rules of engagement apply to diverse RNA helicases and TRIM/TRIM-like proteins. Our analyses thus reveal not only conserved substrates for TRIM proteins but also unexpectedly deep evolutionary connections between TRIM proteins and RNA helicases, thereby linking ubiquitin and RNA biology throughout animal evolution.

scholarly journals TRIM29 in Cutaneous Squamous Cell Carcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Che-Yuan Hsu ◽  
Teruki Yanagi ◽  
Hideyuki Ujiie
Keyword(s):  
Malignant Tumors ◽  
Coiled Coil ◽  
Dna Damage Signaling ◽  
Physiological Processes ◽  
Trim Protein ◽  
Coiled Coil Domain ◽  
Zinc Finger Motifs ◽  
Wide Range ◽  
Trim Proteins

Tripartite motif (TRIM) proteins play important roles in a wide range of cell physiological processes, such as signal transduction, transcriptional regulation, innate immunity, and programmed cell death. TRIM29 protein, encoded by the ATDC gene, belongs to the RING-less group of TRIM protein family members. It consists of four zinc finger motifs in a B-box domain and a coiled-coil domain, and makes use of the B-box domain as E3 ubiquitin ligase in place of the RING. TRIM29 was found to be involved in the formation of homodimers and heterodimers in relation to DNA binding; additional studies have also demonstrated its role in carcinogenesis, DNA damage signaling, and the suppression of radiosensitivity. Recently, we reported that TRIM29 interacts with keratins and FAM83H to regulate keratin distribution. Further, in cutaneous SCC, the expression of TRIM29 is silenced by DNA methylation, leading to the loss of TRIM29 and promotion of keratinocyte migration. This paper reviews the role of TRIM family proteins in malignant tumors, especially the role of TRIM29 in cutaneous SCC.

scholarly journals TRIM protein domain topology and implications for antiviral immunity

2014 ◽  
Vol 70 (a1) ◽  
pp. C243-C243
Author(s):  
David Jacques ◽  
Cy Jeffries ◽  
Matthew Caines ◽  
Michael Lammers ◽  
Donna Mallery ◽  
...  
Keyword(s):  
Domain Architecture ◽  
Coiled Coil ◽  
Antiviral Immunity ◽  
Protein Domain ◽  
Titration Calorimetry ◽  
Protein Chain ◽  
Trim Protein ◽  
Tripartite Motif ◽  
Trim Proteins ◽  
Terminal Domains

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.

Abstract 86: Compromised Sarcolemmal Membrane Repair Contributes to the Progression of Heart Failure

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Sayak Bhattacharya ◽  
Zhaobin Xu ◽  
Liubov Gushchina ◽  
Prasanthi Appikatla ◽  
Eric X Beck ◽  
...  
Keyword(s):  
Heart Failure ◽  
Membrane Damage ◽  
Cardiac Injury ◽  
Human Myocardium ◽  
Membrane Repair ◽  
Repair Capacity ◽  
Sarcolemmal Membrane ◽  
Downstream Target ◽  
Signaling Axis ◽  
Membrane Resealing

A conserved sarcolemmal membrane repair response exist to counteract membrane damage and restore membrane barrier function in order to maintain normal cellular homeostasis. This response can involve various mechanisms including activation of signaling pathways that trigger vesicular trafficking to the site of injury followed by vesicular fusion with the damaged portion of the membrane to patch the membrane disruption. Previous studies indicate that compromised repair capacity can exacerbate cardiac injury while increasing membrane repair capacity can reduce cardiac pathology. In our studies, membrane repair assays on cardiac and non-cardiac cell lines demonstrated that this process is dependent on activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling axis through the downstream target Akt1. One mechanism found to increase membrane repair following PI3K/Akt1 activation is elevated exocytotic and endocytotic activity. Further studies indicate that the PI3K/Akt1 pathway is relevant to membrane repair in native hearts. Thick slices of myocardium from explanted human and mouse hearts were probed using multi-photon microscopy to determine the membrane repair capacity. These studies indicate decreased repair capacity in failing human myocardium as well as in mouse hearts following transaortic constriction (TAC). This membrane repair response requires PI3K/Akt1 signaling as genetically modified mice null for Akt1 show compromised sarcolemmal membrane repair. Additionally, PI3K or Akt1 inhibition prevents membrane resealing in non-failing human or mouse myocardium. The compromised membrane repair observed in failing human myocardium can be ameliorated by PI3K or Akt1 agonists. Treatment of TAC mice with multiple therapeutic compounds known to increase membrane repair capacity can minimize the development of structural and functional hallmarks of heart failure. Our results indicate that failing cardiomyocytes exhibit compromised membrane repair and that increased PI3K/Akt1 signaling can increase repair capacity thereby demonstrating potential as a heart failure treatment.

Emerging Role of TRIM Family Proteins in Cardiovascular Disease

Cardiology ◽  
2020 ◽  
Vol 145 (6) ◽  
pp. 390-400
Author(s):  
Jing-rui Zhang ◽  
Xin-xin Li ◽  
Wan-ning Hu ◽  
Chang-yi Li
Keyword(s):  
Heart Development ◽  
Cell Protein ◽  
Ion Channel Regulation ◽  
E3 Ligases ◽  
Therapeutic Implications ◽  
Signal Transduction Protein ◽  
Trim Proteins ◽  
Ring E3 Ligases ◽  
Ring E3

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.

Abstract 359: Tripartite Motif Protein 58 (trim58) is a Novel Regulator of Membrane Repair With Increased Expression in Failing Cardiac Muscle

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Karthikeyan Krishnamurthy ◽  
Jenna Alloush ◽  
Zhaobin Xu ◽  
Eric X Beck ◽  
Peter J Mohler ◽  
...  
Keyword(s):  
Heart Failure ◽  
Striated Muscle ◽  
Muscle Cells ◽  
Repair Process ◽  
Protein Profiling ◽  
Negative Regulator ◽  
Membrane Repair ◽  
Repair Capacity ◽  
Sarcolemmal Membrane ◽  
Tripartite Motif

In recent years, members of the tripartite motif-containing (TRIM) family of E3 ubiquitin ligases have been shown to be both positively and negatively regulated in various disease pathologies. TRIM72 (MG53) has been directly linked with regulation of sarcolemmal membrane repair in striated muscle cells, including cardiomyocytes. Recently, we were first to identify that a novel tripartite motif family member, TRIM58, is a negative regulator of the cell membrane repair process in striated muscle cells. Overexpression of TRIM58 decreases the membrane repair capacity of cultured myoblasts as measured by dye occlusion following laser-mediated disruption of the sarcolemmal membrane. We also find that TRIM58 can directly interact with TRIM72/MG53 and alter signaling through phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K). Protein profiling experiments show that TRIM58 expression increases during the development of heart failure suggesting that TRIM58 may be relevant in the development of cardiac failure. Western blot and histological examination in both human (Fig.1) and mouse transverse aortic constriction (TAC) heart failure samples clearly show an increased expression of TRIM58 in cardiac tissue. Our results suggest that TRIM58 levels might serve as a potential prognostic marker and that TRIM58 may be a therapeutic target for the management of cardiovascular disease.

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