Syncytin, envelope protein of human endogenous retrovirus (HERV): no longer ‘fossil’ in human genome

ABSTRACT Human endogenous retroviruses (HERVs) were first identified almost 20 years ago, and since then numerous families have been described. It has, however, been difficult to obtain a good estimate of both the total number of independently derived families and their relationship to each other as well as to other members of the familyRetroviridae. In this study, I used sequence data derived from over 150 novel HERVs, obtained from the Human Genome Mapping Project database, and a variety of recently identified nonhuman retroviruses to classify the HERVs into 22 independently acquired families. Of these, 17 families were loosely assigned to the class I HERVs, 3 to the class II HERVs and 2 to the class III HERVs. Many of these families have been identified previously, but six are described here for the first time and another four, for which only partial sequence information was previously available, were further characterized. Members of each of the 10 families are defective, and calculation of their integration dates suggested that most of them are likely to have been present within the human lineage since it diverged from the Old World monkeys more than 25 million years ago.

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CSIG-24. TARGETED INHIBITION OF CDK5-MEDIATED REGULATION OF HUMAN ENDOGENOUS RETROVIRUS K (HML-2) ENVELOPE PROTEIN IN ATYPICAL TERATOID RHABDOID TUMOR

Neuro-Oncology ◽

10.1093/neuonc/noab196.150 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi38-vi38

Author(s):

Tara Doucet-O'Hare ◽

Jared Rosenblum ◽

Brianna DiSanza ◽

Catherine DeMarino ◽

Abigail Atkinson ◽

...

Keyword(s):

Cell Viability ◽

Cell Lines ◽

Envelope Protein ◽

Phosphorylation Site ◽

Endogenous Retrovirus ◽

Rhabdoid Tumor ◽

Human Endogenous Retrovirus ◽

Atypical Teratoid Rhabdoid Tumor ◽

Atypical Teratoid ◽

Targeted Inhibition

Abstract Atypical teratoid rhabdoid tumor (ATRT) is a pediatric brain tumor with a high mortality rate characterized by mutations in/ deletions of SWI/SNF matrix-associated actin-dependent regulator of chromatin sub-family B member 1 (SMARCB1). We previously showed that loss of SMARCB1 causes up-regulation and release of HML-2 subfamily of human endogenous retrovirus K envelope protein (HML-2 ENV), resulting in maintenance of pluripotency. Here, we investigated intracellular trafficking and release of HML-2 ENV. Further, we demonstrate two potential therapeutic strategies to decrease intracellular HML-2 ENV: 1) inhibition of calcium influx by ouabain, a cardiac glycoside toxic to neural stem cells, and 2) targeted inhibition of cyclin-dependent kinase 5 (CDK5), which is restricted to neurons by p35, its activator protein, by TP5. ATRT cell lines and tumor tissue obtained from patients were confirmed for SMARCB1 loss and increased HML-2 ENV. Cell viability and intracellular HML-2 ENV concentration were measured after treatment with ouabain and TP5 (CDK5 antagonist). We evaluated the calcium-mediated effect of ouabain on HML-2 intracellular concentration by treating the cells with ouabain, the calcium chelators calcimycin and EGTA, and calpeptin, a calpain inhibitor, which activates CDK5, and measuring HML-2 ENV and p35. We evaluated HML-2 ENV for a CDK5 consensus phosphorylation site and performed co-immunoprecipitation to evaluate direct interaction. We evaluated activity of CDK5 in ATRT cell lines by autoradiography. Both Ouabain and TP5 caused a decrease in cell viability in a dose-dependent manner. Further, ouabain treatment decreased HML-2 ENV intracellular concentration. We found that HML-2 ENV contains a consensus phosphorylation site for CDK5. We discovered that HML-2 ENV was bound to CDK5. We established that ATRT cell lines had hyperactive CDK5. Finally, we established that the effect of ouabain on HML-2 ENV was due to indirect inhibition of calcium-mediated activation of calpain and thus CDK5.

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The HERV-K Human Endogenous Retrovirus Envelope Protein Antagonizes Tetherin Antiviral Activity

Journal of Virology ◽

10.1128/jvi.02234-14 ◽

2014 ◽

Vol 88 (23) ◽

pp. 13626-13637 ◽

Cited By ~ 20

Author(s):

C. Lemaitre ◽

F. Harper ◽

G. Pierron ◽

T. Heidmann ◽

M. Dewannieux

Keyword(s):

Antiviral Activity ◽

Envelope Protein ◽

Endogenous Retrovirus ◽

Human Endogenous Retrovirus

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Human Endogenous Retrovirus Family HERV-K(HML-5): Status, Evolution, and Reconstruction of an Ancient Betaretrovirus in the Human Genome

Journal of Virology ◽

10.1128/jvi.78.16.8788-8798.2004 ◽

2004 ◽

Vol 78 (16) ◽

pp. 8788-8798 ◽

Cited By ~ 32

Author(s):

Laurence Lavie ◽

Patrik Medstrand ◽

Werner Schempp ◽

Eckart Meese ◽

Jens Mayer

Keyword(s):

Human Genome ◽

Germ Line ◽

Consensus Sequence ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Open Reading Frames ◽

Primer Binding Site ◽

Human Endogenous Retrovirus ◽

New World Primates ◽

Human Endogenous Retroviruses

ABSTRACT The human genome harbors numerous distinct families of so-called human endogenous retroviruses (HERV) which are remnants of exogenous retroviruses that entered the germ line millions of years ago. We describe here the hitherto little-characterized betaretrovirus HERV-K(HML-5) family (named HERVK22 in Repbase) in greater detail. Out of 139 proviruses, only a few loci represent full-length proviruses, and many lack gag protease and/or env gene regions. We generated a consensus sequence from multiple alignment of 62 HML-5 loci that displays open reading frames for the four major retroviral proteins. Four HML-5 long terminal repeat (LTR) subfamilies were identified that are associated with monophyletic proviral bodies, implying different evolution of HML-5 LTRs and genes. Sequence analysis indicated that the proviruses formed approximately 55 million years ago. Accordingly, HML-5 proviral sequences were detected in Old World and New World primates but not in prosimians. No recent activity is associated with this HERV family. We also conclude that the HML-5 consensus sequence primer binding site is identical to methionine tRNA. Therefore, the family should be designated HERV-M. Our study provides important insights into the structure and evolution of the oldest betaretrovirus in the primate genome known to date.

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A Single Amino Acid Substitution in a Segment of the CA Protein within Gag That Has Similarity to Human Immunodeficiency Virus Type 1 Blocks Infectivity of a Human Endogenous Retrovirus K Provirus in the Human Genome

Journal of Virology ◽

10.1128/jvi.01439-08 ◽

2008 ◽

Vol 83 (2) ◽

pp. 1105-1114 ◽

Cited By ~ 14

Author(s):

David J. Heslin ◽

Pablo Murcia ◽

Frederick Arnaud ◽

Koenraad Van Doorslaer ◽

Massimo Palmarini ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Amino Acid ◽

Human Genome ◽

Particle Production ◽

Endogenous Retrovirus ◽

Single Amino Acid ◽

Human Endogenous Retrovirus ◽

C Terminus ◽

Immunodeficiency Virus

ABSTRACT Human endogenous retrovirus K (HERV-K) is the most intact retrovirus in the human genome. However, no single HERV-K provirus in the human genome today appears to be infectious. Since the Gag protein is the central component for the production of retrovirus particles, we investigated the abilities of Gag from two HERV-K proviruses to support production of virus-like particles and viral infectivity. HERV-K113 has full-length open reading frames for all viral proteins, while HERV-K101 has a full-length gag open reading frame and is expressed in human male germ cell tumors. The Gag of HERV-K101 allowed production of viral particles and infectivity, although at lower levels than observed with a consensus sequence Gag. Thus, including HERV-K109, at least two HERV-K proviruses in human genome today have functional Gag proteins. In contrast, HERV-K113 Gag supported only very low levels of particle production, and no infectivity was detectable due to a single amino acid substitution (I516M) near the extreme C terminus of the CA protein within Gag. The sequence of this portion of HERV-K CA showed similarities to that of human immunodeficiency virus type 1 and other primate immunodeficiency viruses. The extreme C terminus of CA may be a general determinant of retrovirus particle production. In addition, precise mapping of the defects in HERV-K proviruses as was done here identifies the key polymorphisms that need to be analyzed to assess the possible existence of infectious HERV-K alleles within the human population.

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Human Endogenous Retrovirus HERV-K14 Families: Status, Variants, Evolution, and Mobilization of Other Cellular Sequences

Journal of Virology ◽

10.1128/jvi.79.5.2941-2949.2005 ◽

2005 ◽

Vol 79 (5) ◽

pp. 2941-2949 ◽

Cited By ~ 20

Author(s):

Aline Flockerzi ◽

Stefan Burkhardt ◽

Werner Schempp ◽

Eckart Meese ◽

Jens Mayer

Keyword(s):

Human Genome ◽

Germ Line ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Human Endogenous Retrovirus ◽

Long Terminal Repeats ◽

Essential Information ◽

Human Endogenous Retroviruses ◽

Consensus Sequences

ABSTRACT The human genome harbors many distinct families of human endogenous retroviruses (HERVs) that stem from exogenous retroviruses that infected the germ line millions of years ago. Many HERV families remain to be investigated. We report in the present study the detailed characterization of the HERV-K14I and HERV-K14CI families as they are represented in the human genome. Most of the 68 HERV-K14I and 23 HERV-K14CI proviruses are severely mutated, frequently displaying uniform deletions of retroviral genes and long terminal repeats (LTRs). Both HERV families entered the germ line ∼39 million years ago, as evidenced by homologous sequences in hominoids and Old World primates and calculation of evolutionary ages based on a molecular clock. Proviruses of both families were formed during a brief period. A majority of HERV-K14CI proviruses on the Y chromosome mimic a higher evolutionary age, showing that LTR-LTR divergence data can indicate false ages. Fully translatable consensus sequences encoding major retroviral proteins were generated. Most HERV-K14I loci lack an env gene and are structurally reminiscent of LTR retrotransposons. A minority of HERV-K14I variants display an env gene. HERV-K14I proviruses are associated with three distinct LTR families, while HERV-K14CI is associated with a single LTR family. Hybrid proviruses consisting of HERV-K14I and HERV-W sequences that appear to have produced provirus progeny in the genome were detected. Several HERV-K14I proviruses harbor TRPC6 mRNA portions, exemplifying mobilization of cellular transcripts by HERVs. Our analysis contributes essential information on two more HERV families and on the biology of HERV sequences in general.

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Expression of Human Endogenous Retrovirus Type K Envelope Protein is a Novel Candidate Prognostic Marker for Human Breast Cancer

Genes & Cancer ◽

10.1177/1947601911431841 ◽

2011 ◽

Vol 2 (9) ◽

pp. 914-922 ◽

Cited By ~ 40

Author(s):

J. Zhao ◽

K. Rycaj ◽

S. Geng ◽

M. Li ◽

J. B. Plummer ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Marker ◽

Envelope Protein ◽

Human Breast Cancer ◽

Endogenous Retrovirus ◽

Human Endogenous Retrovirus ◽

Human Breast ◽

Type K

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An N-terminally truncated envelope protein encoded by a human endogenous retrovirus W locus on chromosome Xq22.3

Retrovirology ◽

10.1186/1742-4690-7-69 ◽

2010 ◽

Vol 7 (1) ◽

pp. 69 ◽

Cited By ~ 22

Author(s):

Christina Roebke ◽

Silke Wahl ◽

Georg Laufer ◽

Christine Stadelmann ◽

Marlies Sauter ◽

...

Keyword(s):

Envelope Protein ◽

Endogenous Retrovirus ◽

Human Endogenous Retrovirus

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Comprehensive Characterization of the Human Endogenous Retrovirus HERV-K(HML-6) Group: Overview of Structure, Phylogeny, and Contribution to the Human Genome

Journal of Virology ◽

10.1128/jvi.00110-19 ◽

2019 ◽

Vol 93 (16) ◽

Cited By ~ 7

Author(s):

Maria Paola Pisano ◽

Nicole Grandi ◽

Marta Cadeddu ◽

Jonas Blomberg ◽

Enzo Tramontano

Keyword(s):

Human Genome ◽

Germ Line ◽

Endogenous Retrovirus ◽

Endogenous Retroviruses ◽

Human Endogenous Retrovirus ◽

Genomic Context ◽

Reading Frame ◽

Normal Tissues ◽

Small Proteins ◽

Human Genes

ABSTRACTEight percent of the human genome is composed of human endogenous retroviruses (HERVs), remnants of ancestral germ line infections by exogenous retroviruses, which have been vertically transmitted as Mendelian characters. The HML-6 group, a member of the class II betaretrovirus-like viruses, includes several proviral loci with an increased transcriptional activity in cancer and at least two elements that are known for retaining an intact open reading frame and for encoding small proteins such as ERVK3-1, which is expressed in various healthy tissues, and HERV-K-MEL, a small Env peptide expressed in samples of cutaneous and ocular melanoma but not in normal tissues.IMPORTANCEWe reported the distribution and genetic composition of 66 HML-6 elements. We analyzed the phylogeny of the HML-6 sequences and identified two main clusters. We provided the first description of a Rec domain within theenvsequence of 23 HML-6 elements. A Rec domain was also predicted within the ERVK3-1 transcript sequence, revealing its expression in various healthy tissues. Evidence about the context of insertion and colocalization of 19 HML-6 elements with functional human genes are also reported, including the sequence 16p11.2, whose 5′ long terminal repeat overlapped the exon of one transcript variant of a cellular zinc finger upregulated and involved in hepatocellular carcinoma. The present work provides the first complete overview of the HML-6 elements in GRCh37(hg19), describing the structure, phylogeny, and genomic context of insertion of each locus. This information allows a better understanding of the genetics of one of the most expressed HERV groups in the human genome.

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