A primate-specific endogenous retroviral envelope protein sequesters SFRP2 to regulate human cardiomyocyte development
Ran Zhang, Menghua Wu, Dan Xiang, Jieying Zhu, Qi Zhang, Hui Zhong, Yuling Peng, Zhenhua Wang, Gang Ma, Guihuan Li, Fengping Liu, Weipeng Ye, Ruona Shi, Xuemeng Zhou, Isaac A. Babarinde, Huanxing Su, Jiekai Chen, Xiaofei Zhang, Dajiang Qin, Andrew P. Hutchins, Duanqing Pei, Dongwei Li
Abstract
Endogenous retroviruses (ERVs) occupy a significant part of the human genome, with some encoding proteins that influence the immune system or regulate cell-cell fusion in early extra-embryonic development. However, whether ERV-derived proteins regulate somatic development is unknown. Here, we report a somatic developmental function for the primate-specific ERVH48-1 (SUPYN/Suppressyn). ERVH48-1 encodes a fragment of a viral envelope that is expressed during early embryonic development. Loss of ERVH48-1 led to impaired mesoderm and cardiomyocyte commitment and diverted cells to an ectoderm-like fate. Mechanistically, ERVH48-1 is localized to sub-cellular membrane compartments through a functional N-terminal signal peptide and binds to the WNT antagonist SFRP2 to promote its polyubiquitination and degradation, thus limiting SFRP2 secretion and blocking repression of WNT/β-catenin signaling. Knockdown of SFRP2 or expression of a chimeric SFRP2 with the ERVH48-1 signal peptide rescued cardiomyocyte differentiation. This study demonstrates how ERVH48-1 modulates WNT/β-catenin signaling and cell type commitment in somatic development.