Alternative titles; symbols
HGNC Approved Gene Symbol: TRIM5
Cytogenetic location: 11p15.4 Genomic coordinates (GRCh38) : 11:5,588,635-5,685,074 (from NCBI)
TRIM5 belongs to the large tripartite motif protein family, members of which typically are composed of 3 zinc-binding domains, a RING, unique B-box type 1 and B-box type 2 domains, followed by a coiled-coil (CC) region. TRIM proteins use homomultimerization to identify specific cell compartments.
Using a consensus B-box domain to screen dbEST databases, Reymond et al. (2001) identified 37 TRIM members in mammals, 21 of which were novel, as well as 34 splice variants. TRIM5 has 6 variants termed alpha, beta, gamma, delta, epsilon, and zeta, all of which lack a B-box type 1 domain. Additional domains C-terminal to the CC region are variably present. TRIM5-zeta lacks RING, B-box, and CC domains, but possesses 3 RFP-like domains. Northern blot analysis of adult human tissues detected ubiquitous expression of TRIM5. Using interaction mating and mutation analysis, Reymond et al. (2001) confirmed that TRIM5, like most TRIMs, homointeracts through the CC region. Interaction was also detected with TRIM6 (607564). Green fluorescent protein microscopy demonstrated expression as cytoplasmic speckles, possibly in novel subcellular compartments.
Stremlau et al. (2004) determined that human TRIM5-alpha contains 493 amino acids and includes a C-terminal b30.2 (SPRY) domain missing in other TRIM5 isoforms.
By fluorescence microscopy and mutation analysis, Xu et al. (2003) showed that TRIM5-delta interacts with BTBD1 (608530) and BTBD2 (608531), apparently serving as a scaffold for the assembly of endogenous BTBD1/2 proteins, dependent on the presence of the CC region and a wildtype RING domain. TRIM5-delta exhibits ubiquitylation in the presence of UBCH5B (UBE2D2; 602962), dependent on the presence of zinc-coordinating cysteines in the RING domain.
Kaiser et al. (2007) reported the reconstruction of the core protein of a 4-million-year-old endogenous virus from the chimpanzee genome (PtERV1) and showed that the human variant of the intrinsic immune protein TRIM5-alpha can actively prevent infection by this virus. However, Kaiser et al. (2007) suggested that the selective changes that have occurred in the human lineage during the acquisition of resistance to this virus, and perhaps similar viruses, may have left our species more susceptible to infection by HIV-1.
Pertel et al. (2011) demonstrated that TRIM5 promotes innate immune signaling and that this activity is amplified by retroviral infection and interaction with the capsid lattice. Acting with the heterodimeric ubiquitin-conjugating enzyme UBC13-UEV1A, TRIM5 catalyzes the synthesis of unattached K63-linked ubiquitin chains that activate the TAK1 (602614) kinase complex and stimulate AP1 (see 165160) and NF-kappa-B (see 164011) signaling. Interaction with the HIV-1 capsid lattice greatly enhanced the UBC13-UEV1A-dependent E3 activity of TRIM5, and challenge with retroviruses induced the transcription of AP1- and NF-kappa-B-dependent factors with a magnitude that tracked with TRIM5 avidity for the invading capsid. Finally, TAK1 and UBC13-UEV1A contributed to capsid-specific restriction by TRIM5. Pertel et al. (2011) concluded that the retroviral restriction factor TRIM5 has 2 additional activities that are linked to restriction: it constitutively promotes innate immune signaling, and it acts as a pattern recognition receptor specific for the retrovirus capsid lattice.
Ribeiro et al. (2016) demonstrated that human E3-ubiquitin ligase TRIM5-alpha potently restricts HIV-1 infection of Langerhans cells but not of subepithelial DCSIGN (CD209; 604672)+ dendritic cells. HIV-1 restriction by TRIM5-alpha had been considered to be reserved to nonhuman primate TRIM5-alpha orthologs, but the data strongly suggested that human TRIM5-alpha is a cell-specific restriction factor dependent on C-type lectin receptor function. Ribeiro et al. (2016) suggested that their findings highlighted the importance of HIV-1 binding to langerin (604862) for the routing of HIV-1 into the human TRIM5-alpha-mediated restriction pathway. TRIM5-alpha mediates the assembly of an autophagy-activating scaffold to langerin, which targets HIV-1 for autophagic degradation and prevents infection of Langerhans cells. By contrast, HIV-1 binding to DCSIGN+ dendritic cells leads to disassociation of TRIM5-alpha from DCSIGN, which abrogates TRIM5-alpha restriction. Thus, the data of Ribeiro et al. (2016) strongly suggested that restriction by human TRIM5-alpha is controlled by C-type lectin receptor-dependent uptake of HIV-1, dictating protection or infection of human dendritic cell subsets. Therapeutic interventions that incorporate C-type lectin receptors and autophagy-targeting strategies could thus provide cell-mediated resistance to HIV-1 in humans.
By radiation hybrid analysis, Reymond et al. (2001) mapped the TRIM5 gene to chromosome 11p15, in a cluster with TRIM6, TRIM21 (109092), TRIM22 (606559), TRIM34 (605684), and a TRIM pseudogene. The authors noted that, apart from another cluster in the HLA region (chromosome 6p21-23), TRIM genes are dispersed throughout the genome.
Stremlau et al. (2004) noted that HIV-1, the cause of acquired immunodeficiency syndrome (AIDS) in humans, efficiently enters the cells of Old World monkeys but encounters a block before reverse transcription. The block acts on the HIV-1 capsid and is mediated by a dominant repressive factor. By screening HeLa cell lines transduced with a cDNA library from rhesus fibroblasts, Stremlau et al. (2004) identified HeLa cells expressing rhesus TRIM5-alpha. These cells were resistant to HIV-1 but not simian immunodeficiency virus (SIV) infection. PCR analysis indicated a disruption of viral cDNA synthesis in rhesus TRIM5-alpha-expressing cells. Mutation analysis suggested that both the N-terminal RING and C-terminal SPRY domains of rhesus TRIM5-alpha contribute to its HIV-1 inhibitory activity. Short interfering (si) RNA experiments reducing rhesus TRIM5-alpha expression resulted in increased efficiency of HIV-1 infection. Stremlau et al. (2004) concluded that monkey TRIM5-alpha is the repressive factor inhibiting HIV-1 reverse transcription and proposed that rhesus TRIM5-alpha may directly bind and ubiquitinate the HIV-1 viral capsid.
Sayah et al. (2004) showed that knockdown of owl monkey CYPA (123840) by RNA interference (RNAi) correlated with suppression of anti-HIV-1 activity. However, reintroduction of CYPA to RNAi-treated cells did not restore antiviral activity. A search for additional RNAi targets identified TRIMCYP, an RNAi-responsive mRNA encoding a TRIM5/CYPA fusion protein. TRIMCYP accounts for post-entry restriction of HIV-1 in owl monkeys and blocks HIV-1 infection when transferred to otherwise infectable human or rat cells. Sayah et al. (2004) suggested that TRIMCYP arose after the divergence of New and Old World primates when a LINE-1 retrotransposon catalyzed the insertion of a CYPA cDNA into the TRIM5 locus. They concluded that this was the first vertebrate example of a chimeric gene generated by this mechanism of exon shuffling.
Sakuma et al. (2007) showed that rhesus Trim5-alpha, but not human TRIM5-alpha, blocked late-phase HIV-1 production through rapid degradation of HIV-1 Gag polyproteins. In agreement with Sakuma et al. (2007), Zhang et al. (2008) found that rhesus Trim5-alpha could block late-stage HIV-1, but not macaque SIV, production. However, the amount of Trim5-alpha required for this effect was much higher than that endogenously expressed, and they questioned the biologic significance of the finding. In a reply, Sakuma et al. (2008) suggested that technical differences, such as cell lines and capsid sequences, may explain the need for high Trim5-alpha expression in the experiments of Zhang et al. (2008).
Kaiser, S. M., Malik, H. S., Emerman, M. Restriction of an extinct retrovirus by the human TRIM5-alpha antiviral protein. Science 316: 1756-1758, 2007. Note: Erratum: Science 317: 1036 only, 2007. [PubMed: 17588933] [Full Text: https://doi.org/10.1126/science.1140579]
Pertel, T., Hausmann, S., Morger, D., Zuger, S., Guerra, J., Lascano, J., Reinhard, C., Santoni, F. A., Uchil, P. D., Chatel, L., Bisiaux, A., Albert, M. L., Strambio-De-Castillia, C., Mothes, W., Pizzato, M., Grutter, M. G., Luban, J. TRIM5 is an innate immune sensor for the retrovirus capsid lattice. Nature 472: 361-365, 2011. [PubMed: 21512573] [Full Text: https://doi.org/10.1038/nature09976]
Reymond, A., Meroni, G., Fantozzi, A., Merla, G., Cairo, S., Luzi, L., Riganelli, D., Zanaria, E., Messali, S., Cainarca, S., Guffanti, A., Minucci, S., Pelicci, P. G., Ballabio, A. The tripartite motif family identifies cell compartments. EMBO J. 20: 2140-2151, 2001. [PubMed: 11331580] [Full Text: https://doi.org/10.1093/emboj/20.9.2140]
Ribeiro, C. M. S., Sarrami-Forooshani, R., Setiawan, L. C., Zijlstra-Willems, E. M., van Hamme, J. L., Tigchelaar, W., van der Wel, N. N., Kootstra, N. A., Gringhuis, S. I., Geijtenbeek, T. B. H. Receptor usage dictates HIV-1 restriction by human TRIM5-alpha in dendritic cell subsets. Nature 540: 448-452, 2016. [PubMed: 27919079] [Full Text: https://doi.org/10.1038/nature20567]
Sakuma, R., Noser, J. A., Ohmine, S., Ikeda, Y. Rhesus monkey TRIM5-alpha restricts HIV-1 production through rapid degradation of viral Gag polyproteins. Nature Med. 13: 631-635, 2007. [PubMed: 17435772] [Full Text: https://doi.org/10.1038/nm1562]
Sakuma, R., Ohmine, S., Mael, A. A., Noser, J. A., Ikeda, Y. Reply to Zhang et al. (Letter) Nature Med. 14: 236-238, 2008.
Sayah, D. M., Sokolskaja, E., Berthoux, L., Luban, J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 430: 569-573, 2004. [PubMed: 15243629] [Full Text: https://doi.org/10.1038/nature02777]
Stremlau, M., Owens, C. W., Perron, M. J., Kiessling, M., Autissier, P., Sodroski, J. The cytoplasmic body component TRIM5-alpha restricts HIV-1 infection in Old World monkeys. Nature 427: 848-853, 2004. [PubMed: 14985764] [Full Text: https://doi.org/10.1038/nature02343]
Xu, L., Yang, L., Moitra, P. K., Hashimoto, K., Rallabhandi, P., Kaul, S., Meroni, G., Jensen, J. P., Weissman, A. M., D'Arpa, P. BTBD1 and BTBD2 colocalize to cytoplasmic bodies with the RBCC/tripartite motif protein, TRIM5-delta. Exp. Cell Res. 288: 84-93, 2003. [PubMed: 12878161] [Full Text: https://doi.org/10.1016/s0014-4827(03)00187-3]
Zhang, F., Perez-Caballero, D., Hatziioannou,T., Bieniasz, P. D. No effect of endogenous TRIM5-alpha on HIV-1 production. (Letter) Nature Med. 14: 235-236, 2008. [PubMed: 18323834] [Full Text: https://doi.org/10.1038/nm0308-235]