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

Abstract

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.

USP9X deubiquitinase couples the pluripotency network and cell metabolism to regulate ESC differentiation potential

“…Our data suggest an additional function in ESC, with a new layer of regulation involving the regulation of LEFTY2 abundance, a secreted ligand that may act through cell autonomous and non-autonomous functions to regulate ESC fate. We also confirmed previous studies indicating a function of USP9X in mTOR signalling in stem/progenitor cells and its interaction with PEG proteins [51,52,63].…”

“…Co-immunoprecipitation assays followed by proteomic identified numerous proteins interacting with USP9X in ESC, and most of these interaction are disrupted by the deletion of exon 2 of Usp9X or when cells enter differentiation upon LIF removal. A recent study reported USP9X potential binding partners in ESC using a flag-tag inserted in frame in Usp9X exon 2 [63]. The study reported far less USP9X potential binding partners compared to our work, most of which are detected in the Usp9X E2/Y background.…”

“…Importantly, we detected in USP9X precipitates, pluripotency transcription factors SALL4 and OCT4 as well as Gag proteins PEG10 and PEG3, as previously reported in ESC ( Supplementary Table 5A-B) [63,64].…”

Global proteomics ofUbqln2-based murine models of ALS

“…PEG10-RF1/2 is, like the ancestral Gag-Pol protein, generated by a highly efficient translational frameshift between the Gag-like and Pol-like elements (Clark et al, 2007;Shigemoto et al, 2001). While in retroviruses the Pol element is subsequently cleaved from the Gag element, this proteolytic cleavage is at best weak in PEG10 (Abed et al, 2019). Instead, the "Gag-only" form PEG10-RF1 is produced when the frameshift element is bypassed and the proximal stop codon is engaged (Supplemental Figure 4C).…”

“…PEG10 upregulation promotes proliferation and invasiveness of cancer cells (Akamatsu et al, 2015), and deletion in mouse models causes lethality due to placentation defects (Ono et al, 2006). Recently, it was found that PEG10 regulates mRNA abundance in murine trophoblast cells, thereby promoting their differentiation in culture (Abed et al, 2019). Furthermore, purification of PEG10-RF1 yielded virus-like particles (Abed et al, 2019), similar to the Gag-like protein ARC/ARG3.1, which binds RNAs and facilitates intercellular RNA transport among neurons (Ashley et al, 2018;Pastuzyn et al, 2018).…”