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

doi:10.1371/journal.pone.0214110

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

PLoS One. 2019 Apr 5;14(4):e0214110. doi: 10.1371/journal.pone.0214110. eCollection 2019.

Authors

Mona Abed¹, Erik Verschueren², Hanna Budayeva², Peter Liu², Donald S Kirkpatrick², Rohit Reja³, Sarah K Kummerfeld³, Joshua D Webster⁴, Sarah Gierke⁴, Mike Reichelt⁴, Keith R Anderson⁵, Robert J Newman⁵, Merone Roose-Girma⁵, Zora Modrusan⁵, Hazal Pektas⁶, Emin Maltepe⁶, Kim Newton¹, Vishva M Dixit¹

Affiliations

¹ Physiological Chemistry Department, Genentech, South San Francisco, California, United States of America.
² Protein Chemistry Department, Genentech, South San Francisco, California, United States of America.
³ Bioinformatics and Computational Biology Department, Genentech, South San Francisco, California, United States of America.
⁴ Pathology Department, Genentech, South San Francisco, California, United States of America.
⁵ Molecular Biology Department, Genentech, South San Francisco, California, United States of America.
⁶ The Center for Reproductive Sciences, Division of Neonatology, University of California, San Francisco, California, United States of America.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis Regulatory Proteins
Cell Differentiation / genetics*
Cell Lineage / genetics
DNA Transposable Elements / genetics
DNA-Binding Proteins
Female
Gene Expression Regulation, Developmental
Gene Products, gag / genetics
Genomic Imprinting / genetics
Heparin-binding EGF-like Growth Factor / genetics*
Humans
Mice
Nuclear Proteins / genetics*
Placenta / metabolism
Placentation / genetics*
Pregnancy
RNA-Binding Proteins / genetics
Stem Cells / cytology
Stem Cells / metabolism
Transcription Factors / genetics*
Trophoblasts / cytology
Trophoblasts / metabolism

Substances

Apoptosis Regulatory Proteins
DNA Transposable Elements
DNA-Binding Proteins
Gene Products, gag
Hbegf protein, mouse
Heparin-binding EGF-like Growth Factor
Nuclear Proteins
Peg10 protein, mouse
RNA-Binding Proteins
Transcription Factors

Grants and funding

All work was funded by Genentech. Authors MA, EV, HB, PL, DSK, RR, SK, JDW, SG, MR, KRA, RJN, MR-G, ZM, KN, and VMD were employees of Genentech. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.