Functional Study of the Retrotransposon-Derived Human PEG10 Protease

Paternally expressed gene 10 (PEG10) is a human retrotransposon-derived imprinted gene. The mRNA of PEG10 encodes two protein isoforms: the Gag-like protein (RF1(PEG10)) is coded by reading frame 1, while the Gag-Pol-like polyprotein (RF1/RF2(PEG10)) is coded by reading frames 1 and 2. The proteins are translated by a typical retroviral frameshift mechanism. The protease (PR) domain of RF2(PEG10) contains an -Asp-Ser-Gly- sequence, which corresponds to the consensus -Asp-Ser/Thr-Gly- active-site motif of retroviral aspartic proteases. The function of the aspartic protease domain of RF2(PEG10) remains unclear. To elucidate the function of PEG10 protease (PR(PEG10)), we designed a frameshift mutant ((fs)RF1/RF2(PEG10)) for comparison with the RF1/RF2(PEG10) form. To study the effects of PR(PEG10) on cellular proliferation and viability, mammalian HEK293T and HaCaT cells were transfected with plasmids coding for either RF1/RF2(PEG10), the frameshift mutant ((fs)RF1/RF2(PEG10)), or a PR active-site (D370A) mutant (fs)RF1/RF2(PEG10). Our results indicate that (fs)RF1/RF2(PEG10) overexpression results in increased cellular proliferation. Remarkably, transfection with (fs)RF1/RF2(PEG10) had a detrimental effect on cell viability. We hypothesize that PR(PEG10) plays an important role in the function of this retroviral remnant, mediating the proliferation of cells and possibly implicating it in the inhibition of apoptosis.