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  • Review Article
  • Published:

TRIM family proteins and their emerging roles in innate immunity

Key Points

  • The TRIM (tripartite motif-containing) family of proteins is defined by an amino-terminal set of domains that is known as the RBCC (RING, B-box, coiled-coil) motif. The RBCC motif can exist in isolation or in combination with various carboxy-terminal domains.

  • The RING domain of many TRIM proteins has E3 ubiquitin ligase activity that can mediate autoubiquitylation and, less often, sumoylation or ISGylation of the TRIM protein itself and other proteins. The coiled-coil domain promotes self-association and protein oligomerization that can trigger the formation of large protein complexes that are localized to the nucleus or the cytoplasm.

  • Mutations in the TRIM genes MID1 (midline 1), TRIM32 and TRIM37 are responsible for the hereditary genetic diseases X-linked Opitz G/BBB syndrome, limb-girdle muscular dystrophy (type 2H) and Mulibrey nanism, respectively.

  • Many TRIM proteins are responsive to interferon (IFN), with some functioning as downstream effectors of IFN in innate immune responses to retroviruses and other viruses. Members with anti-HIV activity can impede the life cycle of the virus before integration (for example, TRIM5), transcription (for example, TRIM22, TRIM32) and assembly (for example, TRIM22 and TRIM15).

  • Products of other TRIM genes — TRIM21, TRIM25, TRIM27, TRIM30 and TRIM32 — function downstream of IFN and of pathogen-recognition receptors, and modulate innate immune responses to bacterial and viral infections that involve the activation of IFN-regulatory factor 3 (IRF3), IRF7 and nuclear factor-κB (NF-κB).

  • Two TRIM proteins, TRIM21 and TRIM68, are prominent targets of autoantibodies in patients with systemic lupus erythematosus or Sjögren's syndrome.

Abstract

The superfamily of tripartite motif-containing (TRIM) proteins is conserved throughout the metazoan kingdom and has expanded rapidly during vertebrate evolution; there are now more than 60 TRIM proteins known in humans and mice. Many TRIM proteins are induced by type I and type II interferons, which are crucial for many aspects of resistance to pathogens, and several are known to be required for the restriction of infection by lentiviruses. In this Review, we describe recent data that reveal broader antiviral and antimicrobial activities of TRIM proteins and discuss their involvement in the regulation of pathogen-recognition and transcriptional pathways in host defence.

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Figure 1: Effects of human and mouse TRIM proteins on infection with HIV.
Figure 2: TRIM proteins in IFN signalling.
Figure 3: TRIM proteins in TLR, RIG-I and MDA5 signalling pathways.

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Acknowledgements

We thank J. Weddle for his assistance in the preparation of this manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Child Health and Human Development, and National Institute of Allergy and Infectious Diseases.

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Correspondence to Keiko Ozato or Herbert C. Morse III.

Supplementary information

Supplementary information S1 (figure)

Structural features and domain-based classification of TRIM superfamily members. (PDF 163 kb)

Supplementary information S2 (figure)

3D structures of TRIM domains (PDF 199 kb)

Related links

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DATABASES

OMIM

Sjögren's syndrome

X-linked Opitz G/BBB syndrome

FURTHER INFORMATION

GeneCards

HUGO Gene Nomenclature Committee

Tigem website

UniProt Consortium

Glossary

Ubiquitylation

The covalent conjugation of ubiquitin, a 76 amino-acid protein, to other proteins. In addition to targeting proteins for proteasome-mediated degradation, ubiquitylation affects protein stability, trafficking and gene expression, among other functions.

E3 ubiquitin ligase

An enzyme that covalently attaches ubiquitin to specific target proteins at defined lysine residues, resulting in monoubiquitylation, multiubiquitylation or polyubiquitylation of the target protein. E3 ubiquitin ligases act together with a ubiquitin-activating enzyme (E1) and a ubiquitin-conjugating enzyme (E2).

Sumoylation

The post-translational modification of proteins that involves the covalent attachment of small ubiquitin-related modifier 1 (SUMO1)–SUMO4 and that regulates the interactions of those proteins with other macromolecules.

Nuclear bodies

Punctuated, dot-like structures in the nucleus that are visible through a light microscope. The interferon-inducible proteins promyelocytic leukaemia (PML), SP100 and ISG20, as well as SUMO1, are found in nuclear bodies.

Familial Mediterranean fever

(FMF). The most common familial inflammatory disease that is characterized by self-limited attacks of fever and serositis. FMF is transmitted in an autosomal recessive pattern and is caused by mutations in the PRYSPRY domain of the MEFV gene, which encodes the protein pyrin.

Positive selection

A process of natural selection that increases the frequency of beneficial mutations in a population.

p53

A major transcription factor that is activated by numerous genotoxic insults and subsequently induces cell-cycle arrest, cellular senescence or apoptosis. p53 is frequently mutated or functionally inactivated in cancer.

Plasmacytoid DC

A dendritic cell (DC) that is morphologically similar to the antibody-producing plasma cell and produces very high levels of type I interferons (IFNs) in response to viral infection and Toll-like receptor (TLR) stimulation. Plasmacytoid DCs express TLR7 and TLR9, but low levels of TLR3, and the induction of type I IFNs by plasmacytoid DCs does not seem to rely on the retinoic-acid-inducible gene I (RIG-I) signalling pathway.

14-3-3σ

A member of a family of conserved proteins that are present in all eukaryotic organisms and are involved in diverse cellular processes, such as apoptosis, intracellular signalling and cell-cycle regulation. 14-3-3 proteins function as adaptors in protein interactions and can regulate protein localization and enzymatic activity.

Small interfering RNA

Short double-stranded RNAs of 19–23 nucleotides that induce RNA interference, which is a post-transcriptional process that leads to gene silencing in a sequence-specific manner.

Systemic lupus erythematosus

(SLE). SLE is a multigenic, chronic and potentially fatal autoimmune disorder that is characterized by a broad range of clinical abnormalities. SLE can affect nearly all components of the immune system.

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Ozato, K., Shin, DM., Chang, TH. et al. TRIM family proteins and their emerging roles in innate immunity. Nat Rev Immunol 8, 849–860 (2008). https://doi.org/10.1038/nri2413

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