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.

Introduction

Ubiquitination is a mechanism to regulate many cellular processes in eukaryotes. It is catalysed by an enzymatic cascade involving an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin ligase. The tripartite motif (TRIM) subfamily of Really Interesting New Gene (RING) E3 ligases comprises >70 members that regulate a myriad of cellular processes [14]. A recent study showed that nearly half of identified TRIM proteins enhanced innate immune responses, although negative regulatory roles of TRIMs during immune signalling have also been detected [5,6]. Furthermore, there is increasing evidence that implicates TRIM ligases at different levels of the NF-κB signalling pathway, indicating that the negative and positive regulation of immune and inflammatory responses is a key function of this protein family [3,7,8].

TRIM family members share a common domain architecture characterised by the presence of a modular N-terminal RBCC motif, also called the TRIM, which consists of a ‘Really Interesting New Gene’ or RING domain, followed by one or two B-box domains and a long Coiled Coil (CC) region. The RBCC motif is followed by C-terminal functional domains that are often used to categorise family members into subgroups (Figure 1A) [7,9].

Figure 1.

(A) Schematic representation of the domain architecture of TRIM family members together with representative structures for each subdomain: RING domain of TRIM32 (5FEY), tandem B-boxes (B1 and B2) of TRIM18 (2JUN), CC region of TRIM69 (4NQJ) and the PRYSPRY domain (C-terminal domain) of TRIM25 (4B8E). All the structures have been drawn to scale. (B) Structures of TRIM25 in complex with UBE2D1–Ub (5FER). (C) Structure of the CC–PRYSPRY domain construct of TRIM20 (4CG4). (D) Structure of the complex between the PRYSPRY domain of TRIM21 and IgG–Fc (3ZO0). (E) Comparison between the structures of the tandem B-boxes of TRIM18 (2DID) and the structures of the heterodimeric RINGs of BRCA1–BARD1 (1JM7) and Bmi–Ring1B (2CKL). The dimeric structures have been oriented by structurally aligning the B-box1 of TRIM18 with the RING domains of BRCA1 and Bmi1. (F) Examples of C-terminal domains of TRIMs for which structures are available: PHD-bromo domain (cyan) of TRIM24 (3O33), FN3 domain (pink) of TRIM9 (2DB8), filamin domain (green) of TRIM71 (4UMG) and COS domain (yellow) of TRIM18 (5IM8). See also the PRYSPRY domain of TRIM25 in (A).

Figure 1.

(A) Schematic representation of the domain architecture of TRIM family members together with representative structures for each subdomain: RING domain of TRIM32 (5FEY), tandem B-boxes (B1 and B2) of TRIM18 (2JUN), CC region of TRIM69 (4NQJ) and the PRYSPRY domain (C-terminal domain) of TRIM25 (4B8E). All the structures have been drawn to scale. (B) Structures of TRIM25 in complex with UBE2D1–Ub (5FER). (C) Structure of the CC–PRYSPRY domain construct of TRIM20 (4CG4). (D) Structure of the complex between the PRYSPRY domain of TRIM21 and IgG–Fc (3ZO0). (E) Comparison between the structures of the tandem B-boxes of TRIM18 (2DID) and the structures of the heterodimeric RINGs of BRCA1–BARD1 (1JM7) and Bmi–Ring1B (2CKL). The dimeric structures have been oriented by structurally aligning the B-box1 of TRIM18 with the RING domains of BRCA1 and Bmi1. (F) Examples of C-terminal domains of TRIMs for which structures are available: PHD-bromo domain (cyan) of TRIM24 (3O33), FN3 domain (pink) of TRIM9 (2DB8), filamin domain (green) of TRIM71 (4UMG) and COS domain (yellow) of TRIM18 (5IM8). See also the PRYSPRY domain of TRIM25 in (A).

In recent years, increasing structural information has been obtained from different subdomains of TRIM ligases in isolation or bound to protein ligands (Figure 1A–D,F and Table 1). Nevertheless, despite TRIMs representing one of the largest subgroups of RING ligases, only little is known regarding the arrangement of their constituent domains in the context of the entire protein and any potential domain interplay, or their native oligomeric state. Likewise, the contribution of subdomains to cellular activity and substrate ubiquitination is not understood at present.

Table 1
Structural information available on TRIM proteins

Structures in black bold have been solved by X-ray crystallography and the others by NMR spectroscopy. In brackets are the PDB identifiers.

Domain Protein (PDB ID) 
RING TRIM5α (2ECV), TRIM30 (2ECW), TRIM31 (2YSJ/2YSL), TRIM32-core (2CT2), TRIM32-dimer (5FEY), TRIM34 (2EGP), TRIM37 (3LRQ), TRIM39 (2ECJ) 
B-Box TRIM1 (2DJA), TRIM5α (2YRG/5K3Q), TRIM18 (2DQ5/2FFW), TRIM19 (2MVW), TRIM28 (2YVR), TRIM29 (2CSV), TRIM39 (2DID), TRIM41 (2EGM), TRIM54 (3Q1D), TRIM63 (2D8U/3DDT) 
Coiled coil TRIM25 (4LTB/4CFG), TRIM69 (4NQJ) 
C-terminus TRIM1 FN3 (2DMK), TRIM5α PRYSPRY (2LM3/4B3N), TRIM9 FN3 (2DB8), TRIM18 COS (5IM8), TRIM21 PRYSPRY (2VOK), TRIM24 PHD-Bromo (3O33/2YYN), TRIM25 PRYSPRY (4B8E), TRIM28 PHD-Bromo (2RO1), TRIM33 PHD-Bromo (3U5M), TRIM45 filamin (2DS4), TRIM71 filamin (4UMG), TRIM72 PRYSPRY (3KB5) 
Multiple domains TRIM5α B-Box2/CC (4TN3/5EIU/5F7T/5IEA), TRIM18 B-Box1–Box2 (2JUN), TRIM20 CC/PRYSPRY (4CG4) 
TRIM/other protein complexes TRIM5α RING/E2 (4TKP), TRIM21 PRYSPRY/IgGFc (2IWG), TRIM21 PRYSPRY/IgG2a (3ZO0), TRIM25 RING/E2–Ub (5EYA/5FER) 
Domain Protein (PDB ID) 
RING TRIM5α (2ECV), TRIM30 (2ECW), TRIM31 (2YSJ/2YSL), TRIM32-core (2CT2), TRIM32-dimer (5FEY), TRIM34 (2EGP), TRIM37 (3LRQ), TRIM39 (2ECJ) 
B-Box TRIM1 (2DJA), TRIM5α (2YRG/5K3Q), TRIM18 (2DQ5/2FFW), TRIM19 (2MVW), TRIM28 (2YVR), TRIM29 (2CSV), TRIM39 (2DID), TRIM41 (2EGM), TRIM54 (3Q1D), TRIM63 (2D8U/3DDT) 
Coiled coil TRIM25 (4LTB/4CFG), TRIM69 (4NQJ) 
C-terminus TRIM1 FN3 (2DMK), TRIM5α PRYSPRY (2LM3/4B3N), TRIM9 FN3 (2DB8), TRIM18 COS (5IM8), TRIM21 PRYSPRY (2VOK), TRIM24 PHD-Bromo (3O33/2YYN), TRIM25 PRYSPRY (4B8E), TRIM28 PHD-Bromo (2RO1), TRIM33 PHD-Bromo (3U5M), TRIM45 filamin (2DS4), TRIM71 filamin (4UMG), TRIM72 PRYSPRY (3KB5) 
Multiple domains TRIM5α B-Box2/CC (4TN3/5EIU/5F7T/5IEA), TRIM18 B-Box1–Box2 (2JUN), TRIM20 CC/PRYSPRY (4CG4) 
TRIM/other protein complexes TRIM5α RING/E2 (4TKP), TRIM21 PRYSPRY/IgGFc (2IWG), TRIM21 PRYSPRY/IgG2a (3ZO0), TRIM25 RING/E2–Ub (5EYA/5FER) 

Here, we review recent advances made in the structural and functional characterisation of TRIM ligases, which have revealed an unexpected diversity in the role of self-association between different members of this family.

TRIM protein domain architecture

The large majority of TRIM proteins contains an N-terminal RING domain, which confers E3 ligase catalytic activity to this protein family. RING domains are characterised by a conserved pattern of cysteine and histidine residues that co-ordinate two zinc ions in a cross-braced fashion [10]. They recognise the ubiquitin-loaded E2 conjugating enzyme via a conserved surface and mediate ubiquitin transfer onto the substrate (Figure 1B) [11].

Similar to RING domains, B-box domains also coordinate two zinc ions, but lack the E3 catalytic activity of their RING counterpart. Two types of B-boxes — types 1 and 2 — exist with distinct zinc-binding consensus sequences [12]. Many TRIM ligases only contain B-box type 2 (B-box2), whilst those with two B-boxes always contain a tandem B-box1–B-box2 arrangement, suggesting a conserved evolutionary function. The crystal and NMR structures of several isolated B-boxes have been determined, including those of TRIM39 (2DID), TRIM54 (3Q1D) and TRIM63 (3DDT) (Table 1). Currently, only one structure of a tandem B-box is available, the solution structure of B-box1–B-box2 of TRIM18 (2JUN) (Figure 1A) that revealed that the two B-boxes interact with one another in a manner that is reminiscent of the structure of the heterodimeric RING of BRCA1/BARD1 or the Bmi1–Ring1B heterodimer (Figure 1E) [1315].

The central CC region mediates TRIM homodimerisation, and potentially higher order oligomerisation, which is believed to be necessary for their functional activity [16]. Structural studies on the CC regions of TRIM5α (4TN3), TRIM25 (4LTB), TRIM69 (4NQJ) and TRIM20 (4CG4) have shown that the CC adopts an antiparallel dimeric arrangement, placing the RING and B-box domains on opposite sides of the elongated central helical stem, thereby imposing restrictions on the overall protein architecture (Figure 1A,C) [1720]. Based on sequence conservation of the CC region, this antiparallel arrangement is likely to be a common feature of the TRIM family. The functional implications of this architecture will be discussed below.

The variable domains in the C-terminal portion of TRIM proteins constitute the functional units that often mediate target recognition and specificity. TRIM ligases are classified into 11 subgroups according to the type of C-terminal domain present [7]. By far, the most common C-terminal domain is the PRYSPRY, also known as B30.2 domain, which is present in >30 TRIMs (Figure 1A,C) [21]. This domain mediates protein–protein interactions particularly in immune signalling proteins and is present in TRIM proteins either alone or preceded by COS (C-terminal subgroup one signature) and FN3 (Fibronectin type III) domains (Figure 1D) [22]. A similar pattern of domain combination is observed in other subgroups: in TRIM2, 3 and 71, the NHL domain is preceded by a filamin domain, whilst, in TRIM32, the NHL occurs in isolation and immediately follows the RBCC motif [7]. It is worth noting that some TRIM subgroups have only one member, such as the subgroup containing TRIM23 with its ARF (ADP-ribosylation factor) domain or that containing TRIM37 with an MATH (meperin and TRAF homology) domain.

Functional role of TRIM protein subdomains

The RING domain constitutes the catalytic centre of TRIMs. Many RING E3 ligases have been shown to require RING dimerisation as a prerequisite for ubiquitin ligase activity [10,23]. Of the TRIM family RING domains characterised so far, only one has been shown to be a constitutive dimer (TRIM32 and 5FEY) (Figure 1A) [24]. The rest are monomeric in solution at micromolar concentrations, but crystallise as dimers, particularly when in complex with E2 and E2–Ub conjugates such as TRIM5α (4TKP) [25] or TRIM25 (5FER and 5EYA) [24,26]. Nevertheless, dimerisation of these TRIM–RINGs is required for catalytic activity, suggesting that some TRIM ligases are constitutively active, whilst others may only be activated when and where necessary and may require additional levels of regulation (Figure 1B) [2426].

In all TRIM–RING domains characterised so far, dimerisation is mediated by the presence of helical segments flanking either side of the core RING domain: the 40–70 residue-long region that contains the zinc-coordinating residues. Hydrophobic residues within these helical fragments pack against each other to stabilise the dimeric structure [2426]. Deletion of the helical regions of TRIM32 produces a monomeric inactive RING domain (2CT2) [24]. Intriguingly, in the case of TRIM5α and TRIM25, the presence of the N- and C-terminal helices is not sufficient to maintain the RING in a dimeric form in solution (unless at very high concentrations [24]). Instead, extra dimer stabilisation is necessary and seems to be provided by the interaction with the ubiquitin-loaded E2 as observed in the crystal structures [2426].

The interaction between TRIM RING domains and their cognate E2s occurs via a conserved interface that is also observed in other monomeric and dimeric RING–E2 complexes [11]. Furthermore, additional contacts between the dimeric RING domain and ubiquitin stabilise the E2–Ub conjugate in a ‘closed’ conformation in which ubiquitin is activated for transfer as observed also in other dimeric RINGs [24,2628]. Moreover, the recent structure of the RING of TRIM25 in complex with UBE2D1–Ub (5FER, Figure 1B) has shown that an acidic residue in the N-terminal helical segment (E10) is at the centre of a network of interactions that involves residues K11 and K33 of the proximal ubiquitin molecule and N71 of the opposite RING protomer. This interaction further stabilises the E2–Ub ‘closed’ conformation to enhance ubiquitin transfer. Mutations E10R in TRIM25, or E16R in TRIM32, almost completely abolish catalytic activity emphasising the importance of these additional contacts [24]. An identical network of interactions can be observed in the recent crystal structure of the TRIM25–RING domain in complex with UBE2N–Ub [26]. Interestingly, an acidic residue in this position is conserved in nearly all TRIM subgroups containing a PRYSPRY C-terminal domain (subgroups I and IV), but also in many others, suggesting a common mechanism for enhancing ubiquitin transfer [19].

Mutations in some B-boxes have been associated with disease phenotypes, such as P130S in TRIM32 with the Bardet–Biedl syndrome or C142S and C145Y in TRIM18 with the X-linked Opitz G syndrome [2931]. Nevertheless, not much is currently known about their functional role in the context of the full-length protein. Initially, it had been suggested that B-box1 might contribute to the interaction with the cognate E2, whilst B-box2 might regulate catalytic activity, possibly acting as an E4 [12]. However, a more recent study has shown that the presence of B-boxes1 and 2 in TRIM25 or B-box2 in TRIM32 has only a marginal effect on the rate of ubiquitin discharge with ubiquitin-loaded UBE2D1 and has virtually no effect on K63-linked poly-ubiquitin chain formation by the UBE2N/UBE2V1 heterodimer [24]. Moreover, the B-boxes1 of TRIM1 and TRIM18 have been suggested to act as target recognition modules because they bind Alpha4, a regulator of protein phosphatase 2A [32]. B-boxes in other proteins have been implicated in many additional roles, such as transcriptional regulators, protein localisation modules and protein–protein interaction domains, and it remains to be seen if a unified function for this domain exists [13,3335].

TRIM5α is the best characterised member of the TRIM family. Its B-box2 has been shown to contribute to self-association and the ability of TRIM5α to restrict HIV-1 [33,36]. Solution studies and recent crystal structures of dimeric (5EIU) and trimeric forms (5IEA, Figure 2A) of a shorter version of the BCC motif of TRIM5α (‘miniTRIM’) have provided molecular insights into the role of B-box2 in protein trimerisation and retroviral restriction [37,38]. Similarly, the crystal structure of the B-box–CC region of TRIM5α shows that B-box2 is restrained on the elongated CC by hydrophobic contacts with residues in the opposite helical protomer [17]. This ability of B-boxes to self-associate and mediate protein–protein interactions may point to a role as molecular scaffolds to either promote higher order oligomerisation, to contribute to substrate recruitment or, perhaps, act as molecular spacers or pins that restrict the conformational space available to the RING domain, thereby affecting its dynamic behaviour and catalytic capability.

Figure 2.

Schematic representation of possible models for the overall domain architecture of the full-length TRIM25 (A) and TRIM32 (B). (C) Ribbon representation of the structure of the BCC motif of miniTRIM5α (5IEA) [37] and model of the recognition of a viral lattice by a hexagonal TRIM5α lattice. This is shown schematically with the BCC motif of miniTRIM5α and with the structure of the entire CC region [17,37].

Figure 2.

Schematic representation of possible models for the overall domain architecture of the full-length TRIM25 (A) and TRIM32 (B). (C) Ribbon representation of the structure of the BCC motif of miniTRIM5α (5IEA) [37] and model of the recognition of a viral lattice by a hexagonal TRIM5α lattice. This is shown schematically with the BCC motif of miniTRIM5α and with the structure of the entire CC region [17,37].

The elongated CC region of the TRIM family members is both necessary and sufficient for protein homodimerisation. The observed antiparallel helical feature, which positions RING and B-boxes on opposite sides of the molecule, seems to conflict with the need for RING dimerisation as a prerequisite for catalytic activity. Potential mechanisms how RING dimerisation might be facilitated are discussed below.

Many structures of the variable domains that are present in the C-terminal portion of TRIMs are available, but mostly they represent isolated domains (Table 1). At present, the crystal structure of the CC–PRYSPRY fragment of TRIM20 (4CG4) is the only structure that contains the C-terminal functional domain together with the CC region (Figure 1C) [20]. This structure shows the conserved antiparallel CC with the PRYSPRY domain placed in the middle of the long helical stem. Small-angle X-ray scattering data suggest that the domain has a high degree of mobility and exists in an equilibrium between a closed and an active open conformation, which may be required to accommodate a large ligand [20]. TRIM20 lacks the catalytic RING domain common to other TRIM ligases, which is substituted by a pyrin domain, and is hence an unusual TRIM family member. However, the conformational flexibility of the PRYSPRY domain observed in TRIM20 may represent a common feature of TRIM ligases of this subgroup, and further structural studies are necessary to uncover molecular explanations for such a requirement.

Substrates of TRIM ligases in immune signalling

An increasing number of proteins have been confirmed as substrates of specific TRIM ligases. Most of these substrate interactions are mediated through the variable C-terminal domains. Currently, one of the best structurally characterised examples of a complex between a TRIM ligase and its substrate is that of TRIM21 with IgG-bound pathogen (3ZO0, Figure 1D). TRIM21 acts as a cytosolic antibody receptor and binds with high affinity to the Fc portion of IgG, IgA or IgM found on the surface of internalised pathogens [39,40]. The TRIM21/antibody-bound pathogen recognition leads to proteasome-mediated degradation or activation of different immune signalling pathways (including NF-κB, AP-1 and IRF3/5/7) [41]. Molecular insights into the TRIM21/IgG interaction have been obtained through the co-crystal structure of the TRIM21–PRYSPRY and IgG1–Fc domains [42]. The TRIM21–PRYSPRY interface includes aromatic residues that can differ in primary sequence across mammals, but the presence of structurally equivalent residues allows wide cross-species reactivity [42]. This feature sets TRIM21 apart from other Fc receptors and highlights the importance of TRIM21 in orchestrating cytosolic humoral immunity.

TRIM5α recognises the HIV-1 capsid via its PRYSPRY domain and protects the integrity of the host genome (Figure 2B) [43,44]. Residues important for capsid binding are located on flexible loop regions that undergo conformational changes upon interaction with the retrovirus [44]. Interestingly, the isolated PRYSPRY domain binds with very weak affinity to the viral capsid, whilst full-length TRIM5α utilises hexagonal nets to increase avidity and coat the HIV-1 capsid [37,38,4547].

Another well-studied member of the TRIM family is TRIM25, which has been shown to interact via its C-terminal PRYSPRY domain with retinoic acid-inducible gene I product (RIG-I), an intracellular sensor of viral infection. Ubiquitination of RIG-I by TRIM25 activates a downstream signalling cascade that results in the production of type I interferons [48]. The crystal structure of the mouse TRIM25–PRYSPRY (Figure 1A) domain identified key residues involved in its interaction with the N-terminal caspase activation and recruitment domain (CARD) of RIG-I to promote ubiquitination of K172 in the C-terminal CARD [49]. Furthermore, structural studies of the TRIM25/RIG-I complex are required to gain insights into the precise molecular details of this interaction and to test the hypothesis that binding of TRIM25 to RIG-I may induce its oligomerisation and thereby activate its E3 ligase activity.

TRIM self-association and catalytic activity

RING dimerisation appears to be a requirement for TRIM E3 catalytic activity, and recent biochemical and biophysical studies on three different TRIM ligases (TRIM5α, 25 and 32) have suggested three different mechanisms how this might be achieved [2426].

TRIM5α trimerisation via B-box2 assembles a hexagonal lattice that envelopes the surface of the HIV-1 capsid (Figure 2C) [37,47]. This process brings three RING domains from different monomers close together in a configuration that promotes E3 ligase activity [37,38]. Whilst the presence of three RING domains at the hexagonal junctions would seem redundant, it has been suggested that the ‘orphan’ RING domain is preferentially targeted for autoubiquitination, an important mechanism for HIV-1 retroviral restriction [50]. In an alternative model, one could envisage that the restriction imposed on the mobility of the RING domains by the short linker with the B-box2 (∼10 residues) and/or by the spatial restraint of the retroviral capsid results in the possibility of forming catalytically active dimeric RING exclusively on one side of the three-fold axis, oriented towards the functional PRYSPRY domains. So far, TRIM5α is the only member of the TRIM subfamily of E3 ligases to present such a distinct mechanism involving three RING domains, and further studies will be needed to elucidate its role as a restriction factor and investigate if such higher order arrangements also occur in other TRIM ligases.

Unlike the higher order structure observed for TRIM5α, TRIM32 has been shown to form a stable tetrameric structure, in which the two RING domains dimerise intermolecularly at opposite ends of two antiparallel TRIM32 homodimers. This interaction locks the tetrameric arrangement and suggests that TRIM32 is a constitutively active E3 ligase (Figure 2B) [24]. In contrast, TRIM25 exists as a CC-mediated dimer, and for this family member, it has been suggested that the presence of a ∼20 residue-long linker between the RING and B-box1 provides enough conformational flexibility for RING dimerisation to be achieved in an intramolecular fashion, supported by binding to the E2–Ub conjugate and/or the substrate (Figure 2A) [24]. In an alternative model for TRIM25 activity, it was suggested that binding to the RIG-I substrate induces protein tetramerisation, thereby leading to RING dimerisation in a manner similar to TRIM32 [26]. More data are required to support individual models and identify the molecular determinants that underlie these different mechanisms of self-association and regulation of E3 ligase activity.

Pathogen-mediated inhibition of TRIMs

TRIM family E3 ligases play an important role in the regulation of innate immune responses and pathogen evasion. Conversely, pathogens have evolved a range of mechanisms to target host immune responses, which include targeting of TRIM family ligases and the host ubiquitination machinery.

One of the first identified cases of a TRIM ligase being targeted by a pathogen is that of influenza virus A non-structural protein 1 (NS1) that recognises TRIM25 and suppresses signalling downstream from RIG-I and the production of interferon [51]. NS1 has been reported to bind directly to the CC region of TRIM25, which has been suggested to inhibit TRIM25 oligomerisation and thereby its E3 ligase activity that is required to induce an antiviral response. The precise structural and mechanistic details of this interaction remain to be understood.

Similarly, PML (TRIM19) has been shown to form large nuclear aggregates (PML nuclear bodies or PML-NBs) that activate downstream immune responses against viral pathogens, especially human cytomegaloviruses (HCMV) [52,53]. The antiviral function of PML-NBs is antagonised by HCMV primarily through the immediate early protein IE1 [54]. The crystal structure of the central globular domain (IE1CORE) of IE1 revealed that it resembles the structure of a TRIM CC region [55]. Similar to the NS1/TRIM25 interaction, the region of PML recognised by the IE1CORE domain is the CC domain. Complex formation between IE1 and PML abrogates the formation of PML-NBs by sequestering the available pool of PML and thus suppresses innate immune defence mechanisms, but the molecular details of this interaction are also still unknown [55].

Bacteria can also modulate the host immune response by targeting TRIM family proteins, as recently shown in a study that identified TRIM56 and TRIM65 as the targets of Salmonella typhimurium SopA [56]. Ubiquitination of TRIM65 by SopA was shown to enhance its ability to induce interferon-β production, but the molecular details of the SopA–TRIM interaction and the mechanism underlying the observed enhancement of signalling remain to be identified.

Conclusions

Structural information on TRIM proteins has just started to emerge, and further studies will be necessary to fully understand this complex family of proteins that plays such an important role in the regulation of immune signalling pathways. Recent studies have already uncovered an unexpected diversity in the mechanism that links TRIM protein self-association to catalytic activity and substrate recognition, and it will be interesting to see how other family members use the TRIM to carry out their biological role.

Abbreviations

     
  • AP-1

    activator protein 1

  •  
  • ARF

    ADP-ribosylation factor

  •  
  • B-box2

    B-box type 2

  •  
  • CARD

    N-terminal caspase activation and recruitment domain

  •  
  • CC

    Coiled Coil

  •  
  • COS

    C-terminal subgroup one signature

  •  
  • FN3

    Fibronectin type III

  •  
  • HCMVs

    human cytomegaloviruses

  •  
  • IRF

    interferon regulatory factor

  •  
  • MATH

    meperin and TRAF homology

  •  
  • NS1

    non-structural protein 1

  •  
  • PHD

    plant homeodomain

  •  
  • PML-NBs

    PML nuclear bodies

  •  
  • RBCC

    RING/B-box/coiled coil

  •  
  • RIG-I

    retinoic acid-inducible gene I product

  •  
  • RING

    Really Interesting New Gene

  •  
  • TRIM

    tripartite motif.

Funding

This work was supported by the Francis Crick Institute which receives its core funding from Cancer Research UK [FC001142], the UK Medical Research Council [FC001142], and the Wellcome Trust [FC001142] and by a PhD fellowship from the Boehringer Ingelheim Fonds to M.G.K.

Competing Interests

The Authors declare that there are no competing interests associated with the manuscript.

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