Abstract
BackgroundAPOBEC3 cytosine deaminases have been demonstrated to restrict infectivity of a series of retroviruses, with different efficiencies depending on the retrovirus. In addition, APOBEC3 proteins can severely restrict the intracellular transposition of a series of retroelements with a strictly intracellular life cycle, including the murine IAP and MusD LTR-retrotransposons.ResultsHere we show that the IAPE element, which is the infectious progenitor of the strictly intracellular IAP elements, and the infectious human endogenous retrovirus HERV-K are restricted by both murine and human APOBEC3 proteins in an ex vivo assay for infectivity, with evidence in most cases of strand-specific G-to-A editing of the proviruses, with the expected signatures. In silico analysis of the naturally occurring genomic copies of the corresponding endogenous elements performed on the mouse and human genomes discloses "traces" of APOBEC3-editing, with the specific signature of the murine APOBEC3 and human APOBEC3G enzymes, respectively, and to a variable extent depending on the family member.ConclusionThese results indicate that the IAPE and HERV-K elements, which can only replicate via an extracellular infection cycle, have been restricted at the time of their entry, amplification and integration into their target host genomes by definite APOBEC3 proteins, most probably acting in evolution to limit the mutagenic effect of these endogenized extracellular parasites.
Highlights
APOBEC3 cytosine deaminases have been demonstrated to restrict infectivity of a series of retroviruses, with different efficiencies depending on the retrovirus
The life cycle of ERVs includes the formation of virus-like particles (VLPs) that, in several instances – but not systematically – can remain strictly intracellular as observed for the well-characterized murine intracisternal A-particle (IAP) and MusD elements, or that can bud at the cell membrane for an extracellular cycle as observed for the recently identified murine intracisternal A-particle-related envelope-encoding (IAPE; [18]) and the human endogenous retrovirus HERV-K(HML2) elements [19,20]
Restriction of murine and human infectious ERVs by APOBEC3 proteins To assay whether the mouse IAPE element is restricted by APOBEC3 proteins, we used the previously described functional copy of IAPE-D [18] that was cloned under the control of the CMV promoter, and in which a neo resistance gene was inserted in reverse orientation into the env gene (Figure 1A)
Summary
APOBEC3 cytosine deaminases have been demonstrated to restrict infectivity of a series of retroviruses, with different efficiencies depending on the retrovirus. The life cycle of ERVs includes the formation of virus-like particles (VLPs) that, in several instances – but not systematically – can remain strictly intracellular as observed for the well-characterized murine intracisternal A-particle (IAP) and MusD elements (the so-called "intracellularized" ERVs, [15,16,17,18]), or that can bud at the cell membrane for an extracellular cycle as observed for the recently identified murine intracisternal A-particle-related envelope-encoding (IAPE; [18]) and the human endogenous retrovirus HERV-K(HML2) elements [19,20] Most of these elements are no longer active due to the accumulation of inactivating mutations, some of them are still functional and have been cloned, allowing direct ex vivo assay of the effect of APOBEC proteins on their mobility. In silico analyses of the naturally present genomic copies of these elements in the murine genome have revealed "traces" of APOBEC3 editing on these elements ([26]; see [30]), supporting the physiological relevance of the observed ex vivo assays, and the genomic impact of APOBEC3 protein activity
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