A primate-specific endogenous retroviral envelope protein sequesters SFRP2 to regulate human cardiomyocyte development,Cell Stem Cell

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A primate-specific endogenous retroviral envelope protein sequesters SFRP2 to regulate human cardiomyocyte development
Cell Stem Cell ( IF 19.8 ) Pub Date : 2024-08-14 , DOI: 10.1016/j.stem.2024.07.006
Ran Zhang ₁ , Menghua Wu ₂ , Dan Xiang ₃ , Jieying Zhu ₄ , Qi Zhang ₂ , Hui Zhong ₄ , Yuling Peng ₂ , Zhenhua Wang ₂ , Gang Ma ₅ , Guihuan Li ₂ , Fengping Liu ₆ , Weipeng Ye ₂ , Ruona Shi ₇ , Xuemeng Zhou ₅ , Isaac A Babarinde ₅ , Huanxing Su ₈ , Jiekai Chen ₄ , Xiaofei Zhang ₉ , Dajiang Qin ₁₀ , Andrew P Hutchins ₅ , Duanqing Pei ₁₁ , Dongwei Li ₂

Affiliation

Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China; State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China.
CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Hong Kong Institute of Science & Innovation, Guangzhou Institutes of Biomedicine and Health, Guangzhou, Guangdong 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Hong Kong Institute of Science & Innovation, Guangzhou Institutes of Biomedicine and Health, Guangzhou, Guangdong 510530, China.
Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518055, China.
Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China; Faculty of Medicine, Macau University of Science and Technology, Taipa, Macau 999078, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.
Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China; CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Hong Kong Institute of Science & Innovation, Guangzhou Institutes of Biomedicine and Health, Guangzhou, Guangdong 510530, China; University of Chinese Academy of Sciences, Beijing 100049, China.
Key Laboratory of Biological Targeting Diagnosis, Therapy and Rehabilitation of Guangdong Higher Education Institutes, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou 510799, China; Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China.
Laboratory of Cell Fate Control, School of Life Sciences, Westlake University, Hangzhou 310024, China.

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.

中文翻译：

灵长类动物特异性内源性逆转录病毒包膜蛋白隔离 SFRP2 以调节人心肌细胞发育

内源性逆转录病毒（ERV）占据了人类基因组的重要组成部分，其中一些编码的蛋白质会影响免疫系统或在早期胚胎外发育中调节细胞与细胞的融合。然而，ERV 衍生蛋白是否调节体细胞发育尚不清楚。在这里，我们报告了灵长类动物特异性 ERVH48-1 (SUPYN/Suppressyn) 的体细胞发育功能。 ERVH48-1 编码在早期胚胎发育过程中表达的病毒包膜片段。 ERVH48-1 的缺失导致中胚层和心肌细胞的定向受损，并使细胞转向外胚层样的命运。从机制上讲，ERVH48-1通过功能性N端信号肽定位于亚细胞膜区室，并与WNT拮抗剂SFRP2结合，促进其多泛素化和降解，从而限制SFRP2的分泌并阻断WNT/β-连环蛋白信号传导的抑制。 SFRP2 的敲低或带有 ERVH48-1 信号肽的嵌合 SFRP2 的表达可挽救心肌细胞分化。这项研究展示了 ERVH48-1 如何调节体细胞发育中的 WNT/β-连环蛋白信号传导和细胞类型定型。

更新日期：2024-08-14

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