Patterns of Evolution of TRIM Genes Highlight the Evolutionary Plasticity of Antiviral Effectors in Mammals

Abstract

The innate immune system of mammals is formed by a complex web of interacting proteins, which together constitute the first barrier of entry for infectious pathogens. Genes from the E3-ubiquitin ligase tripartite motif (TRIM) family have been shown to play an important role in the innate immune system by restricting the activity of different retrovirus species. For example, TRIM5 and TRIM22 have both been associated with HIV restriction and are regarded as crucial parts of the antiretroviral machinery of mammals. Our analyses of positive selection corroborate the great significance of these genes for some groups of mammals. However, we also show that many species lack TRIM5 and TRIM22 altogether. By analyzing a large number of mammalian genomes, here we provide the first comprehensive view of the evolution of these genes in eutherians, showcasing that the pattern of accumulation of TRIM genes has been dissimilar across mammalian orders. Our data suggest that these differences are caused by the evolutionary plasticity of the immune system of eutherians, which have adapted to use different strategies to combat retrovirus infections. Altogether, our results provide insights into the dissimilar evolution of a representative family of restriction factors, highlighting an example of adaptive and idiosyncratic evolution in the innate immune system.

Capsid-dependent lentiviral restrictions

“…In addition to TRIM5 , primate genomes encode approximately 70–100 other TRIM genes ( 84 ). TRIM5 itself exists in a gene locus with three paralogous TRIM family members (TRIM34 , TRIM6 , and TRIM22) ; these are the most closely related TRIM genes to TRIM5 in the human genome ( 85 , 86 ). TRIM34 was first identified as ring finger 21 in a screen to identify novel RING domain-containing proteins in the human genome ( 87 ).…”

“…In addition to potential functional redundancy, a challenge in assessing the role of TRIMs in restriction phenotypes is that TRIM proteins are known to both homomultimerize and heteromultimerize with other TRIMs as a part of their antiviral function. This heteromultimerization could be important for function as is the case for restriction of HIV-1 CA N74D and SIVs by TRIM34 and TRIM5α ( 41 , 86 , 90 ). Functional studies of TRIM restriction are significantly more complicated if there are more than one TRIM gene involved in a restriction phenotype but approaches to assess heteromultimeric TRIM restriction should be developed and considered in future work.…”

TRIM5α: A Protean Architect of Viral Recognition and Innate Immunity

“…High rates of non-synonymous substitutions per non-synonymous site (dN) to synonymous substitutions (dS) within TRIM5 indicate accelerated protein evolution. It has been estimated that positive selection has shaped the gene for over 77 million years and that this evolutionary influence may be ongoing in many lineages [49]. For example, the cow genome includes five TRIM5 genes, one of which, TRIM5-3, is active against HIV-1 and exhibits an abnormally high dN/dS rate, presumably sampling for better capsidbinding capabilities [50].…”

“…Here, TRIM34, which has not undergone positive selection, utilizes the optimized CA-binding capabilities of TRIM5α to cooperatively function as an antiviral gene [63]. The TRIM6/34/5/22 gene cluster displays remarkably dissimilar patterns of TRIM gene accumulation in mammalian orders, potentially suggesting cooperation in antiviral action in a host-species-specific manner, thus contributing to functional plasticity in innate immunity [49].…”