Intrinsic restriction activity by apolipoprotein B mRNA editing enzyme APOBEC1 against the mobility of autonomous retrotransposons

Abstract

The ability of mammalian cytidine deaminases encoded by the APOBEC3 (A3) genes to restrict a broad number of endogenous retroelements and exogenous retroviruses, including murine leukemia virus and human immunodeficiency virus (HIV)-1, is now well established. The RNA editing family member apolipoprotein B (apo B)-editing catalytic subunit 1 (APOBEC1; A1) from a variety of mammalian species, a protein involved in lipid transport and which mediates C–U deamination of mRNA for apo B, has also been shown to modify a range of exogenous retroviruses, but its activity against endogenous retroelements remains unclear. Here, we show in cell culture-based retrotransposition assays that A1 family proteins from multiple mammalian species can also reduce the mobility and infectivity potential of LINE-1 (long interspersed nucleotide sequence-1, L1) and long-terminal repeats (LTRs) retrotransposons (or endogenous retroviruses), such as murine intracisternal A-particle (IAP) and MusD sequences. The anti-L1 activity of A1 was mainly mediated by a deamination-independent mechanism, and was not affected by subcellular localization of the proteins. In contrast, the inhibition of LTR-retrotransposons appeared to require the deaminase activity of A1 proteins. Thus, the AID/APOBEC family proteins including A1s employ multiple mechanisms to regulate the mobility of autonomous retrotransposons in several mammalian species.

Intrinsic restriction activity by AID/APOBEC family of enzymes against the mobility of retroelements

“…A1 as well as hA3A and hA3G are able to inhibit nascent L1 DNA accumulation, suggesting interference with L1 reverse transcription, integration and/or intracellular movement of L1 ribonucleoprotein particles (RNPs). 14,19 Furthermore, the suppressive activity against de novo L1 DNA synthesis was mainly in a deaminationindependent manner, and was not affected by subcellular localization of the proteins. 14 AID/APOBEC proteins might be able to interact with the cytoplasmic RNPs and interfere with subsequent RNPs transport and/or nuclear import.…”

“…[12][13][14] In addition, several reports indicated that A1s from several mammalian species inhibit a wide range of exogenous retroviruses such as HIV-1. [15][16][17][18] These results raise the possibility that not only A3 proteins but also AID and A1 cytidine deaminases are likely to participate in the intrinsic immunity in various mammalian species against the retrotransposition of endogenous and exogenous retroviruses.…”

“…The catalytic activity of A1s appeared to be critical for these repressive potentials. 14,17 In addition, although the expression of A1 in human has only been formally documented in gastrointestinal tissue, the distribution for mouse, rat and rabbit A1s is much wider, including tissues such as hepatocytes and spleen which are assumed to have little apoB mRNA. Furthermore, A1 mRNA is expressed in ovarian and testis tissue, at least in mouse and rabbit, placing A1 in a compartment where endogenous retrovirus may have the greatest impact in vivo.…”

“…Furthermore, A1 mRNA is expressed in ovarian and testis tissue, at least in mouse and rabbit, placing A1 in a compartment where endogenous retrovirus may have the greatest impact in vivo. 14 Interestingly, the powerful inhibition of endogenous retrovirus by the single-domain cytidine deaminase hA3A appeared to occur independently of only in placental mammals, thus far. In contrast, the single-domain A1 protein with apoB mRNA editing activity appears to be expressed in the marsupial opossum.…”

L1 expression and regulation in humans and rodents

“…Several human APOBEC3 genes (128-133), but not mouse mA3 (129,134), inhibit L1 retrotransposition in vitro. Similarly, the overexpression of APOBEC1 or AID from human, rat and mouse can inhibit the retrotransposition activity of a cloned human L1 in human cell lines (135,136). It is puzzling, however, that L1 inhibition by all these deaminase appears to be independent of their deaminase activity.…”