Cytokine Regulation of env Gene Expression of Human Endogenous Retrovirus-R in Human Vascular Endothelial Cells

Katsumata, Kazuaki; Ikeda, Hitoshi; Sato, Masayuki; Ishizu, Akihiro; Kawarada, Yo; Katô, Hiroaki; Wakisaka, Akemi; Koike, Takao; Yoshiki, Takashi

doi:10.1006/clim.1999.4762

Cited by 50 publications

(53 citation statements)

References 42 publications

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“…This finding is in line with reports showing some dependence of several HERV LTRs on pregnancy hormones and their up-regulation in embryonic tissues (15,54). There is also circumstantial evidence that HERV expression is elevated by proinflammatory cytokines (55,56). A number of studies have, indeed, shown that HERV-encoded proteins are expressed in inflamed tissues, and antibodies to HERVs in patients with autoimmune diseases such as systemic lupus erythematodes (SLE), Sjogren's syndrome, multiple sclerosis, and related dis- eases were frequently detected (46,52,(57)(58)(59)(60).…”

Section: Production Of Herv Particlessupporting

confidence: 91%

Retroelements and the human genome: New perspectives on an old relation

Bannert

Kurth

2004

Proc. Natl. Acad. Sci. U.S.A.

465

423

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Retroelements constitute a large portion of our genomes. One class of these elements, the human endogenous retroviruses (HERVs), is comprised of remnants of ancient exogenous retroviruses that have gained access to the germ line. After integration, most proviruses have been the subject of numerous amplifications and have suffered extensive deletions and mutations. Nevertheless, HERV-derived transcripts and proteins have been detected in healthy and diseased human tissues, and HERV-K, the youngest, most conserved family, is able to form virus-like particles. Although it is generally accepted that the integration of retroelements can cause significant harm by disrupting or disregulating essential genes, the role of HERV expression in the etiology of malignancies and autoimmune and neurologic diseases remains controversial. In recent years, striking evidence has accumulated indicating that some proviral sequences and HERV proteins might even serve the needs of the host and are therefore under positive selection. The remarkable progress in the analysis of host genomes has brought to light the significant impact of HERVs and other retroelements on genetic variation, genome evolution, and gene regulation.A lmost half of the mammalian genome is derived from ancient transposable elements. The two general types, (DNA)-transposons and retroelements, often regarded as ''selfish DNA parasites or junk DNA,'' encompass Ϸ2.8% and 42.2% of the human genome, respectively (1, 2). This striking finding is one of the many insights from recent large-scale sequencing projects that have provided the most valuable information in this field since the initial discovery of mobile elements in 1956 by Barbara McClintock (3, 4). Whereas DNA-transposons amplify without an RNA intermediate, retroelements rely on an RNA transcript that is retrotranscribed by a reverse transcriptase before integration in the genome. Here, we briefly review the characteristics of retroelements, their present classification, and the available evidence for their biological significance and function in normal and pathological processes. The focus is on human endogenous retroviruses (HERVs), the remnants of ancient germ-cell infections. Although most of the HERV proviruses have undergone extensive deletions and mutations, some have retained ORFs coding for functional proteins. A few families, including the HERV-K (HML-2) group, have been shown to form viral particles (5, 6), and an apparently intact provirus has recently been discovered in a small fraction of the human population, indicating a very recent acquisition (5-7). Classification of RetroelementsRetroelements constitute 90% of the Ϸ3 million transposable elements present in the human genome (1). They are split into two large groups, the non-LTR and LTR elements (Fig. 1). Two of the non-LTR members are present in extremely high copy numbers in the mammalian germ line: the short interspersed elements (SINE) with the prominent Alu and MIR repeats and the long-terminal interspersed elements (LINE) containing the...

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Section: Production Of Herv Particlessupporting

confidence: 91%

Retroelements and the human genome: New perspectives on an old relation

Bannert

Kurth

2004

Proc. Natl. Acad. Sci. U.S.A.

465

423

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“…Up-regulation of HERVs has been observed in the context of neuroinflammation (27) and cytokine treatment (28). Earlier studies showed induction of both Syncytin-1 and inducible NO synthase (iNOS) in glial cells in the brains of MS patients, particularly in astrocytes (12,29).…”

Section: Ultiple Sclerosis (Ms)mentioning

confidence: 99%

The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes

Antony

Ellestad

Hammond

et al. 2007

The Journal of Immunology

126

125

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Retroviral envelopes are pathogenic glycoproteins which cause neuroinflammation, neurodegeneration, and endoplasmic reticulum stress responses. The human endogenous retrovirus (HERV-W) envelope protein, Syncytin-1, is highly expressed in CNS glia of individuals with multiple sclerosis (MS). In this study, we investigated the mechanisms by which Syncytin-1 mediated neuroimmune activation and oligodendrocytes damage. In brain tissue from individuals with MS, ASCT1, a receptor for Syncytin-1 and a neutral amino acid transporter, was selectively suppressed in astrocytes (p < 0.05). Syncytin-1 induced the expression of the endoplasmic reticulum stress sensor, old astrocyte specifically induced substance (OASIS), in cultured astrocytes, similar to findings in MS brains. Overexpression of OASIS in astrocytes increased inducible NO synthase expression but concurrently down-regulated ASCT1 (p < 0.01). Treatment of astrocytes with a NO donor enhanced expression of early growth response 1, with an ensuing reduction in ASCT1 expression (p < 0.05). Small-interfering RNA molecules targeting Syncytin-1 selectively down-regulated its expression, preventing the suppression of ASCT1 and the release of oligodendrocyte cytotoxins by astrocytes. A Syncytin-1-transgenic mouse expressing Syncytin-1 under the glial fibrillary acidic protein promoter demonstrated neuroinflammation, ASCT1 suppression, and diminished levels of myelin proteins in the corpus callosum, consistent with observations in CNS tissues from MS patients together with neurobehavioral abnormalities compared with wild-type littermates (p < 0.05). Thus, Syncytin-1 initiated an OASIS-mediated suppression of ASCT1 in astrocytes through the induction of inducible NO synthase with ensuing oligodendrocyte injury. These studies provide new insights into the role of HERV-mediated neuroinflammation and its contribution to an autoimmune disease.

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“…Interleukin 1 (IL-1) induces expression of xenotropic ERV in pancreatic β cells of NOD mice susceptible to IDDM [85]. IL-1 and tumor necrosis factor α (TNFα) stimulate, while IFN-γ inhibits transcription of HERV-R in human vascular endothelial cells [86]. IFN-α induces expression of HERV-K18.1 env, which acting as a superantigen, causes Vβ7- [87] or Vβ13-specific T-cell expansions [88].…”

Section: Immunomodulation By Ervmentioning

confidence: 99%

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

et al. 2008

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Genetic and environmental factors are believed to influence development of systemic lupus erythematosus (SLE). Endogenous retroviruses (ERV) correspond to the integrated proviral form of infectious retroviruses, which are trapped within the genome due to mutations. ERV represent a key molecular link between the host genome and infectious viral particles. ERV-encoded proteins are recognized by antiviral immune responses and become targets of autoreactivity. Alternatively, ERV protein may influence cellular processes and the life cycle of infectious viruses. As examples, the HRES-1 human ERV encodes a 28-kDa nuclear autoantigen and a 24-kDa small GTP-ase, termed HRES-1/Rab4. HRES-1/p28 is a nuclear autoantigen recognized by crossreactive antiviral antibodies, while HRES-1/Rab4 regulates surface expression of CD4 and the transferrin receptor (TFR) through endosome recycling. Expression of HRES-1/Rab4 is induced by the tat gene of HIV-1, which in turn down-regulates expression of CD4 and susceptibility to reinfection by HIV-1. CD4 and the TFR play essential roles in formation of the immunological synapse (IS) during normal T-cell activation by a cognate MHC class II peptide complex. The key intracellular transducer of T-cell activation, Lck, is brought to the IS via binding to CD4. T-cell receptorζ (TCRζ) chain binds to the TFR. Abnormal T-cell responses in SLE have been associated with reduced lck and TCRζ chain levels. HRES-1 is centrally located on chromosome 1 at q42 relative to lupus-linked microsatellite markers and polymorphic HRES-1 alleles have been linked to the development of SLE. 1q42 is one of the three most common fragile sites in the human genome, and is inducible by DNA demethylation, a known mechanism of retroviral gene activation. Molecular mimicry and immunomodulation by a ERV, such as HRES-1, may contribute to self-reactivity and abnormal Tand B-cell functions in SLE. (Table I). HERVs are commonly designated as HERV followed by a single letter amino acid code corresponding to a tRNA. The 3′ terminus of tRNA is predicted to initiate reverse transcription by annealing to an 18 nucleotide long primer-binding site (PBS) at the 5′ LTR. While expression of murine ERV can lead to production of infectious virus and cause viremia, no production of infectious virion has been documented by HERV. High copy number of most ERV families makes it difficult to distinguish which members of a group are expressed. Although, no single provirus with intact LTRs and uninterrupted gag, pol, and env ORFs has been identified, the HERV-K ERV, as a family, has been shown to encode gag HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript the LTR region, is functionally analogous to the HIV-1 rev and HTLV-I/II rex proteins. HERV-K rev binds to both the nuclear export factor Crm1 and to a cis-acting viral RNA to activate nuclear export of unspliced RNAs [39]. Alternatively, the HERV-K LTR is also recognized by HIV-1 rev, suggesting a potential interaction between these exogeneous a...

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Cytokine Regulation of env Gene Expression of Human Endogenous Retrovirus-R in Human Vascular Endothelial Cells

Cited by 50 publications

References 42 publications

Retroelements and the human genome: New perspectives on an old relation

Retroelements and the human genome: New perspectives on an old relation

The Human Endogenous Retrovirus Envelope Glycoprotein, Syncytin-1, Regulates Neuroinflammation and Its Receptor Expression in Multiple Sclerosis: A Role for Endoplasmic Reticulum Chaperones in Astrocytes

Molecular mimicry and immunomodulation by the HRES-1 endogenous retrovirus in SLE

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