广州医科大学李东伟等研究人员合作发现，灵长类动物特异性内源性逆转录病毒包膜蛋白隔离SFRP2以调节人类心肌细胞发育。这一研究成果于2024年8月14日在线发表在国际学术期刊《细胞—干细胞》上。

研究人员报告了灵长类特有的ERVH48-1（SUPYN/Suppressyn）的体细胞发育功能。ERVH48-1编码在胚胎早期发育过程中表达的病毒包膜片段。缺失ERVH48-1会导致中胚层和心肌细胞承诺受损，并使细胞转向类似外胚层的命运。

从机理上讲，ERVH48-1通过功能性N端信号肽定位到亚细胞膜区室，并与WNT拮抗剂SFRP2结合，促进其多泛素化和降解，从而限制SFRP2的分泌，阻断对WNT/β-catenin信号的抑制。敲除SFRP2或表达带有ERVH48-1信号肽的嵌合SFRP2可挽救心肌细胞的分化。

这项研究证明了ERVH48-1如何在体细胞发育过程中调节WNT/β-catenin信号传导和细胞类型确立。

据悉，内源性逆转录病毒（ERV）占据了人类基因组的很大一部分，其中一些编码的蛋白质可影响免疫系统或调节胚外早期发育中的细胞-细胞融合。然而，ERV衍生的蛋白质是否调控体细胞发育尚不清楚。

附：英文原文

Title: A primate-specific endogenous retroviral envelope protein sequesters SFRP2 to regulate human cardiomyocyte development

Author: 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

Issue&Volume: 2024-08-14

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.

DOI: 10.1016/j.stem.2024.07.006

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(24)00256-X