Antiretroelement activity of APOBEC3H was lost twice in recent human evolution.
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ABSTRACT:
SUBMITTER: OhAinle M
PROVIDER: S-EPMC2608726 | biostudies-literature | 2008 Sep
REPOSITORIES: biostudies-literature
Publications
Antiretroelement activity of APOBEC3H was lost twice in recent human evolution.
OhAinle Molly M Kerns Julie A JA Li Melody M H MM Malik Harmit S HS Emerman Michael M
Cell host & microbe 20080901 3
The primate APOBEC3 gene locus encodes a family of proteins (APOBEC3A-H) with various antiviral and antiretroelement activities. Here, we trace the evolution of APOBEC3H activity in hominoids to identify a human-specific loss of APOBEC3H antiviral activity. Reconstruction of the predicted ancestral human APOBEC3H protein shows that human ancestors encoded a stable form of this protein with potent antiviral activity. Subsequently, the antiviral activity of APOBEC3H was lost via two polymorphisms ...[more]
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Project description:Genes in the APOBEC3 family encode cytidine deaminases that provide a barrier against viral infection and retrotransposition. Of all the APOBEC3 genes in humans, APOBEC3H (A3H) is the most polymorphic: some genes encode stable and active A3H proteins, while others are unstable and poorly antiviral. Such variation in human A3H affects interactions with the lentiviral antagonist Vif, which counteracts A3H via proteasomal degradation. In order to broaden our understanding of A3H-Vif interactions, as well as its evolution in Old World monkeys, we characterized A3H variation within four African green monkey (AGM) subspecies. We found that A3H is highly polymorphic in AGMs and has lost antiviral activity in multiple Old World monkeys. This loss of function was partially related to protein expression levels but was also influenced by amino acid mutations in the N terminus. Moreover, we demonstrate that the evolution of A3H in the primate lineages leading to AGMs was not driven by Vif. Our work suggests that the activity of A3H is evolutionarily dynamic and may have a negative effect on host fitness, resulting in its recurrent loss in primates.IMPORTANCE Adaptation of viruses to their hosts is critical for viral transmission between different species. Previous studies had identified changes in a protein from the APOBEC3 family that influenced the species specificity of simian immunodeficiency viruses (SIVs) in African green monkeys. We studied the evolution of a related protein in the same system, APOBEC3H, which has experienced a loss of function in humans. This evolutionary approach revealed that recurrent loss of APOBEC3H activity has taken place during primate evolution, suggesting that APOBEC3H places a fitness cost on hosts. The variability of APOBEC3H activity between different primates highlights the differential selective pressures on the APOBEC3 gene family.
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Project description:The APOBEC3 genes encode cytidine deaminases that act as components of an intrinsic immune defense that have potent activity against a variety of retroelements. This family of genes has undergone a rapid expansion from one or two genes in nonprimate mammals to at least seven members in primates. Here we describe the evolution and function of an uncharacterized antiviral effector, APOBEC3H, which represents the most evolutionarily divergent APOBEC3 gene found in primates. We found that APOBEC3H has undergone significant adaptive evolution in primates. Consistent with our previous findings implicating adaptively evolving APOBEC3 genes as antiviral effectors, APOBEC3H from Old World monkeys (OWMs) has efficient antiviral activity against primate lentiviruses, is sensitive to inactivation by the simian immunodeficiency virus Vif protein, and is capable of hypermutating retroviral genomes. In contrast, human APOBEC3H is inherently poorly expressed in primate cells and is ineffective at inhibiting retroviral replication. Both OWM and human APOBEC3H proteins can be expressed in bacteria, where they display significant DNA mutator activity. Thus, humans have retained an APOBEC3H gene that encodes a functional, but poorly expressed, cytidine deaminase with no apparent antiviral activity. The consequences of the lack of antiviral activity of human APOBEC3H are likely to be relevant to the current-day abilities of humans to combat retroviral challenges.
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