Identification of a post-transcriptional regulatory element in the human endogenous retroviral syncytin-1

Kitao, K.; Tanikaga, Takamasa; Miyazawa, Takayuki

doi:10.1099/jgv.0.001238

Cited by 10 publications

(18 citation statements)

References 26 publications

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“…The SPRE-core motif is functionally essential for the SPRE activity A partial sequence of 3′ end of the ORF and the subsequent 3′ UTR of human syncytin-1 (68-nt) and a partial sequence of 3′ UTR of syncytin-2 (400-nt) increased protein expression when inserted into the 3′ UTR of an HIV-1 Gag expression plasmid (20) (Fig 1A). We speculated that these sequences share functional RNA motifs.…”

Section: Resultsmentioning

confidence: 99%

“…Next, we tried to verify the functional activities of these SPRE-like elements using a reporter assay with HIV-1 Gag as a reporter protein. Since SPRE of syncytin-1 (SPRE-syn1) was identified as a 68-nt sequence including the SPRE-core motif (17-nt) with 5′-flanking (12-nt) and 3′-flanking (39-nt) sequences for enhancing HIV-1 Gag expression (20), we also constructed a reporter plasmid containing SPRE of syncytin-2 (SPRE-syn2) in the same manner (Fig 5A). We applied a recently developed luciferase system called HiBiT (Promega) to quantify the protein amounts by measuring the luminous activities, and HIV-1 Gag was fused with the C-terminal HiBiT tag (HG-HiBiT).…”

Section: Resultsmentioning

confidence: 99%

“…The Syncytin-1 and Syncytin-2 expression plasmids of phCMV3 backbone (#P003300, Genlantis) were constructed previously (20). For minigene construction, ERVWE1 and ERVFRDE1 loci were inserted into the SmaI site of pSP73 (#P2221, Promega) with the fragments of cytomegalovirus (CMV) enhancer and promoter amplified from pcDNA3.1 (#V79020, Thermo Fishier Scientific) using NEBuilder HiFi DNA Assembly Master Mix (#M5520AA, NEB).…”

Section: Discussionmentioning

confidence: 99%

“…Syncytin-1 is an env gene of ERVWE1 and contributes to the cell fusion for the differentiation of multinucleated syncytiotrophoblast in human placenta (18, 19). We have previously reported that an RNA element located in the 3′ end of the ORF and 3′ untranslated region (3′ UTR) of human syncytin-1 is important for its protein expression, and was named s yncytin p osttranscriptional regulatory e lement (SPRE) (20). Indeed, human syncytin-2 , another syncytin gene derived from an env gene of ERVFRDE1 (21) also appears to contain functional motifs in their 3′ UTR necessary for efficient expression (20).…”

Section: Introductionmentioning

confidence: 99%

“…We have previously reported that an RNA element located in the 3′ end of the ORF and 3′ untranslated region (3′ UTR) of human syncytin-1 is important for its protein expression, and was named s yncytin p osttranscriptional regulatory e lement (SPRE) (20). Indeed, human syncytin-2 , another syncytin gene derived from an env gene of ERVFRDE1 (21) also appears to contain functional motifs in their 3′ UTR necessary for efficient expression (20). Such RNA elements would enable us to access to the RNA regulatory mechanisms of ancient retroviruses.…”

Section: Introductionmentioning

confidence: 99%

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An ancient retroviral RNA element hidden in mammalian genomes and its involvement in coopted retroviral gene regulation

Kitao

Nakagawa

Miyazawa

2021

Preprint

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Retroviruses utilize multiple unique RNA elements to control several aspects of RNA processing, such as splicing, subcellular export, and translation. However, it is mostly unclear whether such functional RNA elements are present in endogenous retroviruses (ERVs), many of which were inserted into the host genomes millions of years ago. Previously, in human ERV-derived syncytin-1 gene, we found a cis-acting RNA element named SPRE that enhances its protein expression. In this study, we found a 17-nt common sequence in SPRE of syncytin-1 and another ERV-derived gene, syncytin-2, and the sequence is confirmed to be essential for the expression of the proteins. We detected the sequences of SPRE-like elements in 41 ERV families. Though the SPRE-like elements were not found in currently prevailing (i.e. exogenous) viral sequences, more than thousands of copies of the elements were found in several mammalian genomes, suggesting the ancient integration and propagation of the SPRE-harboring retroviruses in mammalian lineages. Indeed, other mammalian ERV-derived genes: mac-syncytin-3 of macaque, syncytin-Ten1 of tenrec, and syncytin-Car1 of Carnivora contain the SPRE-like elements, and we validated their function for efficient protein expression by in vitro assays. A reporter assay revealed that the enhancement of gene expression by SPRE depended on reporter genes. Moreover, the mutation in SPRE did not affect the gene expression in codon-optimized syncytin-2. However, the same mutation in SPRE impaired the gene expression in wild-type syncytin-2, suggesting that the SPRE dependency of Syncytin-2 expression is due to the negative factors such as inefficient codon frequency or repressive elements within the coding sequence. These results provide new implications that ERVs harbor unique RNA elements involved in the regulation of ERV-derived genes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

An ancient retroviral RNA element hidden in mammalian genomes and its involvement in coopted retroviral gene regulation

Kitao

Nakagawa

Miyazawa

2021

Preprint

Self Cite

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Potentially reduced fusogenicity of syncytin‐2 in New World monkeys

et al. 2023

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Syncytin‐2 is a membrane fusion protein involved in placenta development that is derived from the endogenous retrovirus envelope gene acquired in the common ancestral lineage of New World and Old World monkeys (OWMs). It is known that syncytin‐2 is conserved between apes and OWMs, suggesting its functional importance; however, syncytin‐2 of common marmosets (Callithrix jacchus) exhibits lower fusogenic activity than those of humans and OWMs in human cell lines. To obtain insight into the functional diversity of syncytin‐2 genes in primates, we examined the syncytin‐2 gene in New World monkeys (NWMs). We experimentally evaluated the cell fusion ability of syncytin‐2 in humans, C. jacchus, and tufted capuchins (Sapajus apella). We found that the cell fusion ability of S. apella was lower than that of human syncytin‐2. Chimeric syncytin‐2 constructs revealed that the amino acid differences in the surface unit of S. apella syncytin‐2 were responsible for the weak cell fusion activity. In addition, genomic sequence analyses of syncytin‐2 revealed that the open reading frames (ORFs) of syncytin‐2 were highly conserved in seven apes and 22 OWMs; however, the syncytin‐2 ORFs of three of 12 NWM species were truncated. Our results suggest that syncytin‐2 in several NWMs may be of less importance than in OWMs and apes, and other syncytin‐like genes may be required for placental development in various NWM species.

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Reactivated endogenous retroviruses promote protein aggregate spreading

Liu,

Heumüller,

Hossinger

et al. 2023

Nat Commun

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Prion-like spreading of protein misfolding is a characteristic of neurodegenerative diseases, but the exact mechanisms of intercellular protein aggregate dissemination remain unresolved. Evidence accumulates that endogenous retroviruses, remnants of viral germline infections that are normally epigenetically silenced, become upregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis and tauopathies. Here we uncover that activation of endogenous retroviruses affects prion-like spreading of proteopathic seeds. We show that upregulation of endogenous retroviruses drastically increases the dissemination of protein aggregates between cells in culture, a process that can be inhibited by targeting the viral envelope protein or viral protein processing. Human endogenous retrovirus envelopes of four different clades also elevate intercellular spreading of proteopathic seeds, including pathological Tau. Our data support a role of endogenous retroviruses in protein misfolding diseases and suggest that antiviral drugs could represent promising candidates for inhibiting protein aggregate spreading.

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Identification of a post-transcriptional regulatory element in the human endogenous retroviral syncytin-1

Cited by 10 publications

References 26 publications

An ancient retroviral RNA element hidden in mammalian genomes and its involvement in coopted retroviral gene regulation

An ancient retroviral RNA element hidden in mammalian genomes and its involvement in coopted retroviral gene regulation

Potentially reduced fusogenicity of syncytin‐2 in New World monkeys

Reactivated endogenous retroviruses promote protein aggregate spreading

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