TRIM-proteinfamily

TRIM is the acronym for "tripartite motif containing proteins". The members of the tripartite motif (TRIM) protein family form a diverse group of proteins with different functions. To date, > 70 members of the TRIM protein family have been identified (Bartsch F 2014). All TRIM proteins are characterized by the possession of three distinctive domains: an N-terminal RING-finger domain, one or two B-box domains and a coiled-coil (Reymond et al 2001).

The individual domains are arranged strictly in the same order and at the same position, which does not change even after deletion of individual domains (Ozato et al. 2008). This property has been preserved over the course of evolution. For this reason, it is likely that the tripartite motif is an integrated functional complex rather than a random collection of individual, independent functional domains (Meroni G et al. 2005).

The TRIM protein family can be divided into two groups:

• Into a highly conserved group 1, present in vertebrates and in invertebrates with structural diversity.
• Group 2, which is evolutionarily younger. It is present only in vertebrates and classified by the presence of the SPRY domain, which mediates protein-protein interactions (Tae H et al. 2009).

The genes of the human and murine TRIM protein family are distributed on almost all chromosomes across the entire genome. Gene clusters occur on several chromosomes, such as chromosome 6p21-23 and chromosome 11p15 (Hatakeyama 2011). The clustered genes are often closely related and share a high degree of homology. Positive selection during evolution led to the expansion of the protein family, resulting in the current diversity (Meroni G 2012).

The function of many TRIM proteins has already been described. However, the function of others has remained largely unexplained.

Involvement in essential cellular processes can result in various diseases in the case of genetic dysregulation.

• TRIM18: Mutations of TRIM18 can lead to the development of X-linked Opitz syndrome with malformation of midline structures.

• TRIM20 is associated with familial Mediterranean fever, a chronic febrile illness with secondary amyloidosis.

• TRIM32: Mutations of TRIM32 can lead to Bardet-Biedl syndrome type 11, ciliopathy, or limb-girdle dystrophy (muscle paralysis), depending on the protein domain affected (Saccone et al. 2008).

• TRIM37: Mutations of TRIM37 are responsible for MULIBREY nanism, a dwarfism affecting the muscles, liver, brain, and eyes (Avela et al. 2000).

  TRIM proteins can also cause autoimmune diseases. For example, TRIM21 is a well-studied autoantigen of systemic lupus erythematosus (SLE) and Sjögren's syndrome (Kong et al. 2007).

• TRIM13, TRIM19, TRIM24, TRIM28 and TRIM29: Some TRIM proteins are associated with tumorigenesis and progression. For example, TRIM19, TRIM24, and TRIM27 can fuse with various proteins retinoic acid receptor α, RET=rearranged during transfection, or B-raf =rapidly accelerated fibrosarcoma, isoform B) by chromosomal translocation, thereby exerting oncogenic activity. TRIM13, TRIM19, TRIM24, TRIM28, and TRIM29 regulate the stability and transcription of the tumor suppressor p53.
• TRIM8, TRIM11, TRIM47, and TRIM68: A number of TRIM proteins have been shown to be elementary regulators of cellular processes during metastasis. They exhibit altered activity in different tumor types. In this respect, one hypothesis is that specific TRIM proteins play a crucial role in tumor cell invasion and formation of a metastatic niche. For example, TRIM24 is highly overexpressed in bone metastases from prostate carcinomas. It serves as a prognostic marker. TRIM8, TRIM11, TRIM47, and TRIM68 are other TRIM molecules that are increasingly expressed in prostate carcinoma or influence mechanisms of metastasis.
• Antiviral functions have been described for numerous TRIM proteins (Rajsbaum et al. 2014).
• TRIM5α a well-studied species-specific restriction factor for retroviruses and can block HIV-1 infection in Old World monkeys. Replacement of a single amino acid in the PRY/SPRY domain of TRIM5α mediated inhibition of HIV-1 in humans (Yap et al. 2005). This suggests a species-specific evolutionary process and highlights the importance of the C-terminal PRY/SPRY domain in antiviral restriction (Nisole et al. 2005).
• TRIMs can affect the different stages of viral replication: viral entry, viral gene transcription and viral secretion (Zhang et al. 2006). The increasing number of TRIM proteins demonstrates their role in innate immunity (Rajsbaum et al. 2014). TRIM21: TRIM21 provides a kind of last line of defense against invading viruses, acting here as a sensor that intercepts antibody-coated viruses that have escaped extracellular neutralization and have breached the cell membrane. Upon binding of antibodies attached to viruses, TRIM21 triggers a coordinated and controlled effector and signaling response that prevents viral replication while establishing an antiviral cellular state.
• TRIM27 and TRIM30alpha: The first interactions of TRIM proteins as negative regulators of TLRs were described in 2006 for TRIM27 (Zha et al. 2006) and in 2008 for murine Trim30α. TRIM27 inhibits the TLR signaling cascade as an inhibitor of TLR3-mediated NF-κB activation via interaction with IκB kinases, and Trim30α inhibits the TLR signaling cascade via ubiquitin-mediated lysosomal degradation of the TAB2-TAB3 complex, which limits TRAF6 activity and thus NF-κB.
• TRIM38: In contrast, TRIM38 mediates negative feedback of the TLR signaling cascade via K48-linked ubiquitination of TRAF6. This leads to proteasomal degradation of TRAF6 and thus decreased production of proinflammatory cytokines as a result of inhibited NF-κB as well as MAPK activation (Zhao et al. 2012).
• TRIM23: Additional regulators of the TLR signaling cascade are found in TRIM23, which ubiquitinates NEMO as an activator via K27 and promotes the TLR3-mediated antiviral inflammatory immune response.
• TRIM62 acts as an activator of TLR4-induced NF-κB signaling, likely via TRIF (Uchil et al. 2013). Regulation of TLR2 by TRIM proteins has not been shown to date.
• Various TRIM proteins are thought to play a role in hematopoiesis, such as TRIM28 in murine erythroblast differentiation or TRIM33 and TRIM 58 in hematopoietic stem cell differentiation (Hosoya et al. 2013).

1. Avela K et al (2000) Gene encoding a new RING-B-box coiled-coil protein is mutated in mulibrey nanism. Nat Genet 25: 298-301.
2. Bartsch F (2014) Function and regulation of TRIM58 in myeloid immune defense Inaugural dissertation for the degree of Dr. rer. nat. of the Faculty of Biology at the University of Duisburg-Essen.
3. Foss S et al (2019) TRIM21-From Intracellular Immunity to Therapy. Front. Immunol doi.org/10.3389/fimmu.2019.02049
4. Hatakeyama S (2011). TRIM proteins and cancer. Nat Rev Cancer 11: 792- 804.
5. Hosoya T et al (2013) TRIM28 is essential for erythroblast differentiation in the mouse. Blood 122: 3798- 3807.
6. Kong H J et al (2007). Cutting edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances cytokine expression in macrophages. J Immunol 179: 26-30.
7. Meroni G et al. (2005) TRIM/RBCC, a novel class of 'single protein RING finger' E3 ubiquitin ligases." Bioessays 27: 1147-1157).
8. Meroni G (2012) Genomics and evolution of the TRIM gene family. Adv Exp Med Biol 770: 1-9.
9. Ozato K et al (2008) TRIM family proteins and their emerging roles in innate immunity. Nat Rev Immunol 8: 849-860.
10. Rajsbaum R et al (2008) Type I interferon-dependent and -independent expression of tripartite motif proteins in immune cells. Eur J Immunol 38: 619-630.
11. Saccone V et al (2008). Mutations that impair interaction properties of TRIM32 associated with limb-girdle muscular dystrophy 2H. Hum Mutat 29: 240-247.
12. Tae H ET al. (2009) Ubiquitous SPRY domains and their role in the skeletal type ryanodine receptor. Eur Biophys J 39: 51- 59.
13. Uchil P D et al (2008). TRIM E3 ligases interfere with early and late stages of the retroviral life cycle. PLoS Path 4: e16.
14. Yap M W et al (2005). A single amino acid change in the SPRY domain of human Trim5alpha leads to HIV-1 restriction. Curr Biol 15: 73-78.
15. Zha J et al (2006). The Ret finger protein inhibits signaling mediated by the noncanonical and canonical IkappaB kinase family members. J Immunol 176: 1072-1080.
16. Zhao W et al (2012). E3 ubiquitin ligase tripartite motif 38 negatively regulates TLR-mediated immune responses by proteasomal degradation of TNF receptor-associated factor 6 in macrophages. J Immunol 188: 2567-2574.
17. Zhang F et al (2006). Antiretroviral potential of human tripartite motif-5 and related proteins. Virology 353: 396-409.