Evolution of a TRIM5-CypA Splice Isoform in Old World Monkeys
| Autor: | Laura R. Hall, Shawn P. O'Neil, Michael Farzan, Lu-Ann Pozzi, Andrea Kirmaier, Erez Pery, Welkin E. Johnson, Ruchi M. Newman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
lcsh:Immunologic diseases. Allergy
Genotype Ubiquitin-Protein Ligases Immunology Protein domain Molecular Sequence Data Mutant Chimeric Proteins Cypa HIV Infections Microbiology Macaque Polymorphism Single Nucleotide Evolution Molecular Exon biology.animal Virology Genetics Animals Protein Isoforms Amino Acid Sequence Phytohemagglutinins lcsh:QH301-705.5 Molecular Biology B-Lymphocytes biology Evolutionary Biology/Evolutionary and Comparative Genetics Alternative splicing Homozygote Monkey Diseases Wild type Proteins Cercopithecidae Virology/Mechanisms of Resistance and Susceptibility including Host Genetics biology.organism_classification Immunity Innate Protein Structure Tertiary lcsh:Biology (General) Virology/Immunodeficiency Viruses HIV-1 Leukocytes Mononuclear Virology/Animal Models of Infection Parasitology lcsh:RC581-607 TRIM Motif TRIM Family Cyclophilin A Research Article |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 4, Iss 2, p e1000003 (2008) |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | The TRIM family proteins share a conserved arrangement of three adjacent domains, an N-terminal RING domain, followed by one or two B-boxes and a coiled-coil, which constitutes the tripartite-motif for which the family is named. However, the C-termini of TRIM proteins vary, and include at least nine evolutionarily distinct, unrelated protein domains. Antiviral restriction factor TRIM5α has a C-terminal B30.2/SPRY domain, which is the major determinant of viral target specificity. Here, we describe the evolution of a cyclophilin-A encoding exon downstream of the TRIM5 locus of Asian macaques. Alternative splicing gives rise to chimeric transcripts encoding the TRIM motif fused to a C-terminal CypA domain (TRIM5-CypA). We detected TRIM5-CypA chimeric transcripts in primary lymphocytes from two macaque species. These were derived in part from a CypA pseudogene in the TRIM5 locus, which is distinct from the previously described CypA insertion in TRIM5 of owl monkeys. The CypA insertion is linked to a mutation in the 3′ splice site upstream of exon 7, which may prevent or reduce expression of the α-isoform. All pig-tailed macaques (M. nemestrina) screened were homozygous for the CypA insertion. In contrast, the CypA-containing allele was present in 17% (17/101) of rhesus macaques (M. mulatta). The block to HIV-1 infection in lymphocytes from animals bearing the TRIM5-CypA allele was weaker than that in cells from wild type animals. HIV-1 infectivity remained significantly lower than SIV infectivity, but was not rescued by treatment with cyclosporine A. Thus, unlike owl monkey TRIMCyp, expression of the macaque TRIM5-CypA isoform does not result in increased restriction of HIV-1. Despite its distinct evolutionary origin, Macaca TRIM5-CypA has a similar domain arrangement and shares ∼80% amino-acid identity with the TRIMCyp protein of owl monkeys. The independent appearance of TRIM5-CypA chimeras in two primate lineages constitutes a remarkable example of convergent evolution. Based on the presence of the CypA insertion in separate macaque lineages, and its absence from sooty mangabeys, we estimate that the Macaca TRIM5-CypA variant appeared 5–10 million years ago in a common ancestor of the Asian macaques. Whether the formation of novel genes through alternative splicing has played a wider role in the evolution of the TRIM family remains to be investigated. Author Summary The TRIM5 gene encodes TRIM5α, a protein that blocks infection of the cell by retroviruses. We previously found that the TRIM5α protein of old world monkeys was highly polymorphic. Here, we describe a substitution in a highly conserved, non-coding element normally required for correct splicing of TRIM5α messenger RNA. While it is difficult to prove positive selection for a non-coding change, the frequency of this mutation in two different species of Asian monkeys (Macaca sp) raised the possibility that the mutation was once evolutionarily advantageous. As it turns out, monkeys carrying this substitution also carry a nearby cyclophilin-A (CypA) pseudogene, and these individuals express chimeric mRNA encoding a fusion between the TRIM5 and CypA sequences. Thus, the mutation, which interferes with expression of the normal TRIM5α protein, instead contributes to expression of a novel protein. Remarkably, this is the second example of the appearance of a TRIM5/CypA chimera during primate evolution, the other having occurred in a new world monkey lineage (Aotus sp). Cellular CypA binds to the capsid proteins of several lentiviruses, and we believe that TRIM5-CypA proteins were at one time selected for the ability to block infection by retroviral pathogens, possibly related to modern lentiviruses. |
| Databáze: | OpenAIRE |
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