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2024

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Cell Journal | Li Dongwei/Pei Duanqing/Qin Dajiang/Zhang Xiaofei and other cooperation revealed the key role of endogenous retrovirus ERVH48-1 in primate somatic cell development!

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Endogenous retroviruses (ERVs) occupy an important part of the human genome and encode proteins that influence the immune system or regulate cell-cell fusion in early extraembryonic development. However, (whether ERVs-derived proteins regulate somatic cell development is unclear.

On August 14, 2024, Guangzhou Medical University Li Dongwei, Qin Dajiang, West Lake University Pei Duanqing, South University of Science and Technology Andrew P Hutchins, and Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences Zhang Xiaofei jointly communicated inCell Stem Cell（IF=20）Published online entitled"A primate-specific endogenous retroviral envelope protein sequesters SFRP2 to regulate human cardiomyocyte development"'s research paper,The study foundIsolation of primate-specific endogenous retroviral envelope protein SFRP2 regulates human cardiomyocyte development.

Here, the authors report that primate-specificERVH48-1(SUPYN/Suppressyn).ERVH48-1Encoding viral envelope fragments expressed during early embryonic development.ERVH48-1The deletion of leads to impaired mesodermal and myocardial cell function and diverts the cells to an ectodermal-like fate. Mechanically, ERVH48-1 is located in the subcellular compartment through the functional N-terminal signal peptide, binds to the WNT antagonist SFRP2, promotes its polyubiquitination and degradation, thereby limiting the secretion of SFRP2 and blocking the inhibition of WNT/b-catenin signaling. Knockdown of SFRP2 or expression of SFRP2 chimeric with a ERVH48-1 signal peptide rescues cardiomyocyte differentiation.The study proves thatERVH48-1How to regulate WNT/bβ-catenin signaling and cell-type commitment in somatic cell development.

Endogenous retroviruses (ERVs) are remnants of past retrovirus infections that have integrated into the germline DNA of an organism on an evolutionary timescale. This integration took place over millions of years, giving the organism a rich genomic landscape of viral remains. ERVs constitute an important part of the genome, estimated to account for 5% to 8% in humans. Most ERVs are mutated and do not encode complete proteins; however, non-coding ERVs are involved in a range of cellular and developmental functions, particularly epigenetic control in early embryogenesis.In addition, they can also serve as alternative promoters or enhancers for nearby genes. For example, the human endogenous retrovirus type k (HERV-K) acts as an enhancer recruiting the pluripotent transcription factor OCT4/KLF4 to regulate the embryonic gene expression program. Mouse endogenous retrovirus type 1 (MERVL) and HERV-H are involved in the regulation of three-dimensional chromatin structure during embryonic development.

In the unmutated state, ERVs consist of three major genes: gag, pol, and env, which encode structural proteins, enzymes, and envelope proteins, respectively. Some ERVs in the human genome continue to encode polypeptides and can functionally affect various biological processes. The most characterized ERVs-derived proteins are the syncytin genes (ERVW-1, ERVFRD-1), which encode envelope proteins required for syncytial trophoblast development. These ERVs-derived proteins have been isolated from different viruses many times during mammalian evolution, mediating syncytiotrophoblast invasion.ERVs-Derived Gene ERVH48-1 (Suppressyn/ SUPYN) Involved in Suppression of Cell Fusion During Placental Development Several studies have demonstrated functional roles for other ERVs-derived proteins in extraembryonic tissues.

ERVs have also been reported to mimic exogenous viral threats in the immune system in either beneficial or harmful ways. Recently, Frank et al. reported ERVH48-1 to limit infection by exogenous mammalian type D retroviruses in immune cells. In contrast, expression of ERV sequence fragments is associated with persistent inflammation, false activation of antiviral responses, neurotoxicity, senescence during aging, and cancer development. Non-coding ERVs are widely expressed during mammalian preimplantation development, and protein-coding HERV-K family ERVs can form virus-like particles. However, protein-encoding ERVs are not involved in post-implantation somatic embryo development.
Here, the authors show that the protein encoded by ERVH48-1 is expressed during early human embryonic development and plays a role in cell fate commitment, particularly in mesoderm and cardiomyocyte (CM) differentiation. ERVH48-1 leads to defective β-catenin signaling by sequestering frizzled-related protein 2 (SFRP2) secreted on the membrane compartment and promoting its ubiquitin-mediated degradation. The study found that these effects can be restored by transferring the signal peptide (SP) domain from ERVH48-1 to SFRP2. This discovery not only enriches the understanding of endogenous retroviruses, but also provides a new perspective for future cell development research.

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