Authors
Newman, Ruchi M.Hall, Laura
Kirmaier, Andrea
Pozzi, Lu-Ann M.
Pery, Erez
Farzan, Michael
O'Neil, Shawn P.
Johnson, Welkin E.
UMass Chan Affiliations
Department of PathologyDepartment of Microbiology and Molecular Genetics
Graduate School of Biomedical Sciences
Document Type
Journal ArticlePublication Date
2008-04-05Keywords
Amino Acid Sequence; Animals; B-Lymphocytes; Cercopithecidae; Cyclophilin A; *Evolution, Molecular; Genotype; HIV Infections; HIV-1; Homozygote; Immunity, Innate; Leukocytes, Mononuclear; Molecular Sequence Data; Monkey Diseases; Mutant Chimeric Proteins; Phytohemagglutinins; Polymorphism, Single Nucleotide; Protein Isoforms; Protein Structure, Tertiary; ProteinsLife Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
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 TRIM5alpha 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 alpha-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 approximately 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.Source
PLoS Pathog. 2008 Feb 29;4(2):e1000003. Link to article on publisher's siteDOI
10.1371/journal.ppat.1000003Permanent Link to this Item
http://hdl.handle.net/20.500.14038/32923PubMed ID
18389077; 18389077Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1371/journal.ppat.1000003