Mouse APOBEC3 Restriction of Retroviruses

Abstract

Apolipoprotein B mRNA editing enzyme, catalytic peptide 3 (APOBEC3) proteins are critical host proteins that counteract and prevent the replication of retroviruses. Unlike the genome of humans and other species, the mouse genome encodes a single Apobec3 gene, which has undergone positive selection, as reflected by the allelic variants found in different inbred mouse strains. This positive selection was likely due to infection by various mouse retroviruses, which have persisted in their hosts for millions of years. While mouse retroviruses are inhibited by APOBEC3, they nonetheless still remain infectious, likely due to the actions of different viral proteins that counteract this host factor. The study of viruses in their natural hosts provides important insight into their co-evolution.

Keywords: APOBEC3; cytidine deaminase; mouse mammary tumor virus; murine leukemia virus; restriction factor.

Figure 1

Mouse APOBEC3. (A) Diagram of mAPOBEC3 protein. CD1 encodes the deaminase activity and CD2 is required for packaging into virions. Exon 5 (ex5) is found in proteins made in certain inbred mouse strains. The black arrow points to the possible viral protease (PR) cleavage site in exon 5. (B) Diagram of the intron/exon structure of the two common mApobec3 alleles. Red exons denote polymorphic coding regions. Blue arrows point to the polymorphism at the end of intron 4 that likely influences retention (+exon 5) or skipping (Δexon 5) of the 5th exon. See text for other details. Abbreviations: CD, cytidine deaminase domain; LTR, long terminal repeat.

Figure 2

Mouse mammary tumor virus (MMTV) and murine leukemia virus (MLV) proteins that counteract APOBEC3. (A) Diagram of MLV genome and identified viral anti-APOBEC3 proteins. GlycoGag translation initiation from a CUG upstream from the Gag translation start site. Red lines indicate glycosylation sites. P50 is generated from an alternatively spliced mRNA that results in a protein encoding matrix (MA), p12, the N terminus of capsid (CA) and the C terminus of integrase (IN). The MLV PR has also been shown to degrade APOBEC3. Finally, it has been suggested that MMTV RT prevents APOBEC3 deamination activity by its rapid processivity. (B) The role of glycoGag and P50 in blocking APOBEC3. GlycoGag (red branched lines) prevents APOBEC3 from accessing the reverse transcription complex, and P50 prevents packaging of APOBEC3; both of proteins thereby facilitate reverse transcription in newly infected cells. Reverse transcription is inhibited by APOBEC3 after infection with virions lacking glycoGag, loss of which destabilizes the capsid, or lacking P50.