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Endogenous Retroviruses: Functions at Molecular Level

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 17144

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Special Issue Editor

Dr. Hee-Jae Cha

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Guest Editor

Department of Parasitology and Genetics, College of Medicine, Kosin University, Busan 49104, Republic of Korea
Interests: molecular function of tight junction proteins; CRISPR Cas 9 gene knock out; functional genomics of human endogenous retrovirus
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Endogenous retrovirus genes have become inserted in the human genome for more than one million years. These retroviruses are now inactivated due to mutations, such as deletions or nonsense mutations. After mutation, retroviruses eventually become fixed in the genome in their endogenous form and exist as traces of ancient viruses. Recent studies have shown that these ancient traces of retrovirus still play important roles related to normal physiological function and certain diseases, including cancer. Moreover, endogenous retroviruses regulate host immune systems and interact with active exogenous viruses. In this Special Issue, studies of not only disease-related functions, but also normal physiological functions of endogenous viruses, will be addressed at the molecular level.

Dr. Hee-Jae Cha
Guest Editor

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Keywords

Endogenous retrovirus
Function
Molecular level

Published Papers (5 papers)

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Research

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13 pages, 2187 KiB

Open AccessArticle

Could the Human Endogenous Retrovirus-Derived Syncytialization Inhibitor, Suppressyn, Limit Heterotypic Cell Fusion Events in the Decidua?

by Jun Sugimoto, Sehee Choi, Megan A. Sheridan, Iemasa Koh, Yoshiki Kudo and Danny J. Schust

Int. J. Mol. Sci. 2021, 22(19), 10259; https://doi.org/10.3390/ijms221910259 - 23 Sep 2021

Cited by 7 | Viewed by 2441

Abstract

Proper placental development relies on tightly regulated trophoblast differentiation and interaction with maternal cells. Human endogenous retroviruses (HERVs) play an integral role in modulating cell fusion events in the trophoblast cells of the developing placenta. Syncytin-1 (ERVW-1) and its receptor, solute-linked carrier family A member 5 (SLC1A5/ASCT2), promote fusion of cytotrophoblast (CTB) cells to generate the multi-nucleated syncytiotrophoblast (STB) layer which is in direct contact with maternal blood. Another HERV-derived protein known as Suppressyn (ERVH48-1/SUPYN) is implicated in anti-fusogenic events as it shares the common receptor with ERVW-1. Here, we explore primary tissue and publicly available datasets to determine the distribution of ERVW-1, ERVH48-1 and SLC1A5 expression at the maternal-fetal interface. While SLC1A5 is broadly expressed in placental and decidual cell types, ERVW-1 and ERVH48-1 are confined to trophoblast cell types. ERVH48-1 displays higher expression levels in CTB and extravillous trophoblast, than in STB, while ERVW-1 is generally highest in STB. We have demonstrated through gene targeting studies that suppressyn has the ability to prevent ERVW-1-induced fusion events in co-culture models of trophoblast cell/maternal endometrial cell interactions. These findings suggest that differential HERV expression is vital to control fusion and anti-fusogenic events in the placenta and consequently, any imbalance or dysregulation in HERV expression may contribute to adverse pregnancy outcomes. Full article

(This article belongs to the Special Issue Endogenous Retroviruses: Functions at Molecular Level)

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12 pages, 3386 KiB

Open AccessArticle

HERV-Derived Ervpb1 Is Conserved in Simiiformes, Exhibiting Expression in Hematopoietic Cell Lineages Including Macrophages

by Ayumi Matsuzawa, Jiyoung Lee, So Nakagawa, Johbu Itoh, Mahoko Takahashi Ueda, Satomi Mitsuhashi, Yuta Kochi, Tomoko Kaneko-Ishino and Fumitoshi Ishino

Int. J. Mol. Sci. 2021, 22(9), 4504; https://doi.org/10.3390/ijms22094504 - 26 Apr 2021

Cited by 1 | Viewed by 2576

Abstract

(1) Background: The ERVPb1 gene in humans is derived from an envelope (Env) gene of a human endogenous retrovirus group, HERV-P(b). The ERVPb1 gene reportedly has a conserved open reading frame (ORF) in Old World monkeys. Although its forced expression led to cell-fusion in an ex vivo cell culture system, like other Env-derived genes such as syncytin-1 and -2, its mRNA expression is not placenta-specific, but almost ubiquitous, albeit being quite low in human tissues and organs, implying a distinct role for ERVPb1. (2) Methods: To elucidate the cell lineage(s) in which the ERVPb1 protein is translated in human development, we developed a novel, highly sensitive system for detecting HERV-derived proteins/peptides expressed in the tissue differentiation process of human induced pluripotent stem cells (iPSCs). (3) Results: We first determined that ERVPb1 is also conserved in New World monkeys. Then, we showed that the ERVPb1 protein is translated from a uniquely spliced ERVPb1 transcript in hematopoietic cell lineages, including a subset of macrophages, and further showed that its mRNA expression is upregulated by lipopolysaccharide (LPS) stimulation in primary human monocytes. (4) Conclusions: ERVPb1 is unique to Simiiformes and actually translated in hematopoietic cell lineages, including a subset of macrophages. Full article

(This article belongs to the Special Issue Endogenous Retroviruses: Functions at Molecular Level)

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17 pages, 3337 KiB

Open AccessArticle

Human Endogenous Retrovirus (HERV)-K env Gene Knockout Affects Tumorigenic Characteristics of nupr1 Gene in DLD-1 Colorectal Cancer Cells

by Eun-Ji Ko, Mee-Sun Ock, Yung-Hyun Choi, Juan L. Iovanna, Seyoung Mun, Kyudong Han, Heui-Soo Kim and Hee-Jae Cha

Int. J. Mol. Sci. 2021, 22(8), 3941; https://doi.org/10.3390/ijms22083941 - 11 Apr 2021

Cited by 22 | Viewed by 3472

Abstract

Human endogenous retroviruses (HERVs) are suggested to be involved in the development of certain diseases, especially cancers. To elucidate the function of HERV-K Env protein in cancers, an HERV-K env gene knockout (KO) in DLD-1 colorectal cancer cell lines was generated using the CRISPR-Cas9 system. Transcriptome analysis of HERV-K env KO cells using next-generation sequencing (NGS) was performed to identify the key genes associated with the function of HERV-K Env protein. The proliferation of HERV-K env KO cells was significantly reduced in in vitro culture as well as in in vivo nude mouse model. Tumorigenic characteristics, including migration, invasion, and tumor colonization, were also significantly reduced in HERV-K env KO cells. Whereas, they were enhanced in HERV-K env over-expressing DLD-1 cells. The expression of nuclear protein-1 (NUPR1), an ER-stress response factor that plays an important role in cell proliferation, migration, and reactive oxygen species (ROS) generation in cancer cells, significantly reduced in HERV-K env KO cells. ROS levels and ROS-related gene expression was also significantly reduced in HERV-K env KO cells. Cells transfected with NUPR1 siRNA (small interfering RNA) exhibited the same phenotype as HERV-K env KO cells. These results suggest that the HERV-K env gene affects tumorigenic characteristics, including cell proliferation, migration, and tumor colonization through NUPR1 related pathway. Full article

(This article belongs to the Special Issue Endogenous Retroviruses: Functions at Molecular Level)

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23 pages, 4528 KiB

Open AccessArticle

Formation of HERV-K and HERV-Fc1 Envelope Family Members is Suppressed on Transcriptional and Translational Level

by Victoria Gröger, Lisa Wieland, Marcel Naumann, Ann-Christin Meinecke, Beate Meinhardt, Steffen Rossner, Christian Ihling, Alexander Emmer, Martin S. Staege and Holger Cynis

Int. J. Mol. Sci. 2020, 21(21), 7855; https://doi.org/10.3390/ijms21217855 - 23 Oct 2020

Cited by 9 | Viewed by 3377

Abstract

The human genome comprises 8% sequences of retroviral origin, so-called human endogenous retroviruses (HERVs). Most of these proviral sequences are defective, but some possess open reading frames. They can lead to the formation of viral transcripts, when activated by intrinsic and extrinsic factors. HERVs are thought to play a pathological role in inflammatory diseases and cancer. Since the consequences of activated proviral sequences in the human body are largely unexplored, selected envelope proteins of human endogenous retroviruses associated with inflammatory diseases, namely HERV-K18, HERV-K113, and HERV-Fc1, were investigated in the present study. A formation of glycosylated envelope proteins was demonstrated in different mammalian cell lines. Nevertheless, protein maturation seemed to be incomplete as no transport to the plasma membrane was observed. Instead, the proteins remained in the ER where they induced the expression of genes involved in unfolded protein response, such as HSPA5 and sXBP1. Furthermore, low expression levels of native envelope proteins were increased by codon optimization. Cell-free expression systems showed that both the transcriptional and translational level is affected. By generating different codon-optimized variants of HERV-K113 envelope, the influence of single rare t-RNA pools in certain cell lines was demonstrated. The mRNA secondary structure also appears to play an important role in the translation of the tested viral envelope proteins. In summary, the formation of certain HERV proteins is basically possible. However, their complete maturation and thus full biologic activity seems to depend on additional factors that might be disease-specific and await elucidation in the future. Full article

(This article belongs to the Special Issue Endogenous Retroviruses: Functions at Molecular Level)

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Review

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22 pages, 2140 KiB

Open AccessReview

HSV-1 and Endogenous Retroviruses as Risk Factors in Demyelination

by Raquel Bello-Morales, Sabina Andreu, Inés Ripa and José Antonio López-Guerrero

Int. J. Mol. Sci. 2021, 22(11), 5738; https://doi.org/10.3390/ijms22115738 - 27 May 2021

Cited by 10 | Viewed by 4251

Abstract

Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that can infect the peripheral and central nervous systems, and it has been implicated in demyelinating and neurodegenerative processes. Transposable elements (TEs) are DNA sequences that can move from one genomic location to another. TEs have been linked to several diseases affecting the central nervous system (CNS), including multiple sclerosis (MS), a demyelinating disease of unknown etiology influenced by genetic and environmental factors. Exogenous viral transactivators may activate certain retrotransposons or class I TEs. In this context, several herpesviruses have been linked to MS, and one of them, HSV-1, might act as a risk factor by mediating processes such as molecular mimicry, remyelination, and activity of endogenous retroviruses (ERVs). Several herpesviruses have been involved in the regulation of human ERVs (HERVs), and HSV-1 in particular can modulate HERVs in cells involved in MS pathogenesis. This review exposes current knowledge about the relationship between HSV-1 and human ERVs, focusing on their contribution as a risk factor for MS. Full article

(This article belongs to the Special Issue Endogenous Retroviruses: Functions at Molecular Level)

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