The Gag protein PEG10 binds to RNA and regulates trophoblast stem cell lineage specification

Mona Abed,Erik Verschueren,Hanna Budayeva,Peter Liu,Donald S. Kirkpatrick,Rohit Reja,Sarah K. Kummerfeld,Joshua D. Webster,Sarah Gierke,Mike Reichelt,Keith R. Anderson,Robert J. Newman,Merone Roose-Girma,Zora Modrusan,Hazal Pektas,Emin Maltepe,Kim Newton,Vishva M. Dixit

PLOS   DOI: 10.1371/journal.pone.0214110

Peg10 (paternally expressed gene 10) is an imprinted gene that is essential for placental development. It is thought to derive from a Ty3-gyspy LTR (long terminal repeat) retrotransposon and retains Gag and Pol-like domains. Here we show that the Gag domain of PEG10 can promote vesicle budding similar to the HIV p24 Gag protein. Expressed in a subset of mouse endocrine organs in addition to the placenta, PEG10 was identified as a substrate of the deubiquitinating enzyme USP9X. Consistent with PEG10 having a critical role in placental development, PEG10-deficient trophoblast stem cells (TSCs) exhibited impaired differentiation into placental lineages. PEG10 expressed in wild-type, differentiating TSCs was bound to many cellular RNAs including Hbegf (Heparin-binding EGF-like growth factor), which is known to play an important role in placentation. Expression of Hbegf was reduced in PEG10-deficient TSCs suggesting that PEG10 might bind to and stabilize RNAs that are critical for normal placental development.

Transposable elements (TEs) are one of the biggest threats to the integrity of prokaryotic and eukaryotic genomes because their insertion into coding or regulatory regions could disrupt essential genes [1–3]. Therefore, TEs are often inactivated through mutagenesis [4] or silenced through methylation [5]. Some TEs, however, have been repurposed during evolution for the benefit of the host in a process termed domestication [6], and have important roles in development and immunity [7–10].

In summary, despite its domestication, Peg10 maintains several hallmarks of retroviral and retrotransposon Gag proteins. The Gag domain of PEG10 supports the budding of virus-like particles, which are released from the cell and can be recovered from exosome preparations. ARC (activity regulated cytoskeletal-associated protein) is another retroviral-like Gag protein that drives the budding of extracellular vesicles [51, 52]. ARC, like PEG10, binds to its own mRNA. The release and uptake of Arc-containing VLPs by neurons is considered a mechanism of intercellular communication [51, 52]. Additional work is needed to determine if PEG10 fulfils a similar function.