Functional Study of the Retrotransposon-Derived Human PEG10 Protease.

Mária Golda,József Tőzsér,János András Mótyán,Mohamed Mahdi

doi:10.3390/ijms21072424

Mária Golda, József Tőzsér + Show 2 more

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https://doi.org/10.3390/ijms21072424

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Abstract

Paternally expressed gene 10 (PEG10) is a human retrotransposon-derived imprinted gene. The mRNA of PEG10 encodes two protein isoforms: the Gag-like protein (RF1PEG10) is coded by reading frame 1, while the Gag-Pol-like polyprotein (RF1/RF2PEG10) is coded by reading frames 1 and 2. The proteins are translated by a typical retroviral frameshift mechanism. The protease (PR) domain of RF2PEG10 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 RF2PEG10 remains unclear. To elucidate the function of PEG10 protease (PRPEG10), we designed a frameshift mutant (fsRF1/RF2PEG10) for comparison with the RF1/RF2PEG10 form. To study the effects of PRPEG10 on cellular proliferation and viability, mammalian HEK293T and HaCaT cells were transfected with plasmids coding for either RF1/RF2PEG10, the frameshift mutant (fsRF1/RF2PEG10), or a PR active-site (D370A) mutant fsRF1/RF2PEG10. Our results indicate that fsRF1/RF2PEG10 overexpression results in increased cellular proliferation. Remarkably, transfection with fsRF1/RF2PEG10 had a detrimental effect on cell viability. We hypothesize that PRPEG10 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.

Highlights

Expressed gene 10 (PEG10) is an imprinted gene located on the human chromosome 7q21 and is known to have evolved from a retroviral element, it has lost the ability to replicate independently [1]
We investigated the structural and biochemical characteristics of the aspartic protease domain encoded by the human retrotransposon-derived gene Paternally expressed gene 10 (PEG10)
PRPEG10 was found to show the highest sequence and structural similarity with DNA-damage-inducible 2 (Ddi2) and damage-inducible 1 (Ddi1) PRs [22,27,28]; each of these retroviral-like PRs contains an additional helical insert and has a six-stranded dimer interface organization, which was not found to be characteristic of retroviral PRs [29]

Summary

Introduction

Expressed gene 10 (PEG10) is an imprinted gene located on the human chromosome 7q21 and is known to have evolved from a retroviral element, it has lost the ability to replicate independently [1]. This domesticated retroviral remnant has been shown to be essential for embryonic development in mice; previous studies demonstrated that mutations in the coding sequence of the gene are lethal in the embryonic stage because of defects in placental development [2]. Following the -1 ribosomal frameshift site, RF2PEG10 contains a consensus -Asp-Ser-Gly- sequence motif (Figure 1) that is characteristic of retroviral aspartic proteases; this domain is followed by a truncated reverse transcriptase domain [17]

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