Identification of a Genomic Reservoir for New TRIM Genes in Primate Genomes

Section of Molecular Genetics and Microbiology, Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, USA.
PLoS Genetics (Impact Factor: 7.53). 12/2011; 7(12):e1002388. DOI: 10.1371/journal.pgen.1002388
Source: PubMed


Tripartite Motif (TRIM) ubiquitin ligases act in the innate immune response against viruses. One of the best characterized members of this family, TRIM5α, serves as a potent retroviral restriction factor with activity against HIV. Here, we characterize what are likely to be the youngest TRIM genes in the human genome. For instance, we have identified 11 TRIM genes that are specific to humans and African apes (chimpanzees, bonobos, and gorillas) and another 7 that are human-specific. Many of these young genes have never been described, and their identification brings the total number of known human TRIM genes to approximately 100. These genes were acquired through segmental duplications, most of which originated from a single locus on chromosome 11. Another polymorphic duplication of this locus has resulted in these genes being copy number variable within the human population, with a Han Chinese woman identified as having 12 additional copies of these TRIM genes compared to other individuals screened in this study. Recently, this locus was annotated as one of 34 "hotspot" regions that are also copy number variable in the genomes of chimpanzees and rhesus macaques. Most of the young TRIM genes originating from this locus are expressed, spliced, and contain signatures of positive natural selection in regions known to determine virus recognition in TRIM5α. However, we find that they do not restrict the same retroviruses as TRIM5α, consistent with the high degree of divergence observed in the regions that control target specificity. We propose that this recombinationally volatile locus serves as a reservoir from which new TRIM genes arise through segmental duplication, allowing primates to continually acquire new antiviral genes that can be selected to target new and evolving pathogens.

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Available from: Kyudong Han, Oct 09, 2015
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    • "The TRIM family (tripartite-motif family) of proteins has been reported for their roles in regulating the innate immune response to viral infections [15]. TRIM proteins are structurally characterized by a RING domain, a B-box domain and a coiled-coil domain [16,17]. Functionally, most TRIMs are E3 ubiquitin ligases, where RING domains have ubiquitin ligase activity, while the b-Box domains have interacting motifs. "
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    ABSTRACT: Japanese encephalitis virus (JEV) infection leads to Japanese encephalitis (JE) in humans. JEV is transmitted through mosquitoes and maintained in a zoonotic cycle. This cycle involves pigs as the major reservoir, water birds as carriers and mosquitoes as vectors. JEV invasion into the central nervous system (CNS) may occur via antipodal transport of virions or through the vascular endothelial cells. Microglial cells get activated in response to pathogenic insults. JEV infection induces the innate immune response and triggers the production of type I interferons. The signaling pathway of type I interferon production is regulated by a number of molecules. TRIM proteins are known to regulate the expression of interferons; however, the involvement of TRIM genes and their underlying mechanism during JEV infection are not known. Human microglial cells (CHME3) were infected with JEV to understand the role of TRIM21 in JEV infection and its effect on type I interferon (IFN-beta) production. Cells were infected in presence and absence of exogenous TRIM21 as well as after knocking down the TRIM21 mRNA. Levels of activated IRF3 expression were measured through Western blot analyses of anti-p-IRF3 antibody, and IFN-beta production was measured by using IFN-beta real-time PCR and luciferase activity analyses. JEV infection increased expression of TRIM21 in CHME3 cells. JEV induced an innate immune response by increasing production of IFN-beta via IRF3 activation and phosphorylation. Overexpression of TRIM21 resulted in downregulation of p-IRF3 and IFN-beta, while silencing led to increased production of p-IRF3 and IFN-beta in JEV-infected CHME3 cells. This report demonstrates TRIM21 as a negative regulator of interferon-beta (IFN- beta) production mediated by IRF-3 during JEV infection in human microglial cells.
    Journal of Neuroinflammation 02/2014; 11(1):24. DOI:10.1186/1742-2094-11-24 · 5.41 Impact Factor
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    • "For commercial re-use, please contact TRIM5 is a member of the TRIM multigene family, which encodes as many as 100 genes in humans and is similarly expansive throughout primates (Han et al. 2011). Proteins encoded by the TRIM multigene family are characterized by a tripartite motif consisting of a RING domain, one or two B-boxes, and a Coiled-Coil motif, the order and spacing of which are generally conserved (Reymond et al. 2001; Meroni and Diez-Roux 2005; Nisole et al. 2005). "
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    ABSTRACT: Recurrent viral pressure has acted on host-encoded antiviral genes during primate and mammalian evolution. This selective pressure has resulted in dramatic episodes of adaptation in host antiviral genes, often detected via positive selection. These evolutionary signatures of adaptation have the potential to highlight previously unrecognized antiviral genes (also called restriction factors). While the TRIM multigene family is recognized for encoding several bona fide restriction factors (e.g. TRIM5alpha), most members of this expansive gene family remain uncharacterized. Here, we investigated the TRIM multigene family for signatures of positive selection in order to identify novel candidate antiviral genes. Our analysis reveals previously undocumented signatures of positive selection in 17 TRIM genes, 10 of which represent novel candidate restriction factors. These include the unusual TRIM52 gene, which has evolved under strong positive selection despite its encoded protein lacking a putative viral recognition (B30.2) domain. We show that TRIM52 arose via gene duplication from the TRIM41 gene. Both TRIM52 and TRIM41 have dramatically expanded RING domains compared to the rest of the TRIM multigene family, yet this domain has evolved under positive selection only in primate TRIM52, suggesting that it represents a novel host-virus interaction interface. Our evolutionary-based screen not only documents positive selection in known TRIM restriction factors but also highlights candidate novel restriction factors, providing insight into the interfaces of host-pathogen interactions mediated by the TRIM multigene family.
    Genome Biology and Evolution 10/2013; 5(11). DOI:10.1093/gbe/evt163 · 4.23 Impact Factor
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    • "At latest count, the human TRIM family comprises ~100 genes [66]. Like other members of this large family, TRIM5 possesses an N-terminal RING domain, a B-box domain, and a coiled-coil domain. "
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    ABSTRACT: The past ten years have seen an explosion of information concerning host restriction factors that inhibit the replication of HIV-1 and other retroviruses. Among these factors is TRIM5, an innate immune signaling molecule that recognizes the capsid lattice as soon as the retrovirion core is released into the cytoplasm of otherwise susceptible target cells. Recognition of the capsid lattice has several consequences that include multimerization of TRIM5 into a complementary lattice, premature uncoating of the virion core, and activation of TRIM5 E3 ubiquitin ligase activity. Unattached, K63-linked ubiquitin chains are generated that activate the TAK1 kinase complex and downstream inflammatory mediators. Polymorphisms in the capsid recognition domain of TRIM5 explain the observed species-specific differences among orthologues and the relatively weak anti-HIV-1 activity of human TRIM5. Better understanding of the complex interaction between TRIM5 and the retrovirus capsid lattice may someday lead to exploitation of this interaction for the development of potent HIV-1 inhibitors.
    05/2012; 2012(6):426840. DOI:10.1155/2012/426840
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