Biochemical Analysis of the Complex between the Tetrameric Export Adapter Protein Rec of HERV-K/HML-2 and the Responsive RNA Element RcRE pck30

Langner, Janina S.; Fuchs, Nina V.; Hoffmann, Jan; Wittmann, Alexander; Brutschy, Bernhard; Löwer, Roswitha; Suess, Beatrix

doi:10.1128/jvi.00121-12

Cited by 10 publications

(9 citation statements)

References 47 publications

(72 reference statements)

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“…The NLS also recognizes the Rec-responsive element (RcRE) within the viral RNAs (vRNAs). Rec forms tetramers and, presumably, three tetramers bind to purine-rich stretches within the RcRE (Langner et al 2012). To achieve its nucleocytoplasmic function Rec interacts with Staufen-1, which is also involved in utilization of the cargo RNA for efficient transport and particle encapsidation (Hanke, Hohn, et al 2013).…”

Section: Hml-2 Structure: Genes Transcripts and Proteinsmentioning

confidence: 99%

Human endogenous retrovirus-K (HML-2): a comprehensive review

García-Montojo

Doucet-O’Hare

Henderson

et al. 2018

Critical Reviews in Microbiology

161

164

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The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these are defective or silenced through epigenetic changes, they were historically considered “junk DNA” and their potential role in human physiology or pathological circumstances have been poorly studied. The most recently acquired, human endogenous retrovirus-K (HERV-K), has multiple copies in the human genome and some of them have complete open reading frames that are transcribed and translated, especially in early embryogenesis. Phylogenetically, HERV-K is considered a supergroup of viruses. One of the subtypes, termed HML-2, seems to be the most active and hence, it is the best studied. Aberrant expression of HML-2 in adult tissues has been associated with certain types of cancer and with neurodegenerative diseases. This review discusses the discovery of these viruses, their classification, structure, regulation and potential for replication, physiological roles, and their involvement in disease pathogenesis. Finally, it presents different therapeutic approaches being considered to target these viruses.

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Section: Hml-2 Structure: Genes Transcripts and Proteinsmentioning

confidence: 99%

Human endogenous retrovirus-K (HML-2): a comprehensive review

García-Montojo

Doucet-O’Hare

Henderson

et al. 2018

Critical Reviews in Microbiology

161

164

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“…The mechanism(s) responsible for the difference in relative HIV-1 Rev or HERV-K Rec activity when paired with different HERV-K RcREs was not examined in this study. It has been previously proposed that different stem-loops in the prototypical HERV-K RcRE sequence may be involved in binding to Rev and Rec (31,60,61). For HIV-1 Rev, it has been suggested that there may be two discrete binding sites that lie within stem-loop 2 and 6, while for HERV-K Rec, binding between the protein and RNA may be much more complex, involving folding and three-dimensional structure rather than discrete binding sites within the HERV-K RcRE.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

Gray¹,

Jackson²,

Jackson³

et al. 2019

Preprint

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BackgroundThe HERV-K (HML-2) viruses are the youngest of the human endogenous retroviruses. They are present as several almost complete proviral copies and numerous fragments in the human genome. Many HERV-K proviruses express a regulatory protein Rec, which binds to an element present in HERV-K mRNAs called the RcRE. This interaction is necessary for the nucleo-cytoplasmic export and expression of HERV-K mRNAs that retain introns and plays a role analogous to that of Rev and the RRE in HIV replication. There are over 900 HERV-K RcREs distributed throughout the human genome. Thus, it was of interest to determine if Rev could functionally interact with selected RcRE elements that map either to HERV-K proviruses or human gene regions. This interaction would have the potential to alter the expression of both HERV-K mRNAs and cellular mRNAs during HIV-1 infection. ResultsIn this study we employed a combination of RNAseq, bioinformatics and cell-based functional assays. Potential RcREs were identified through a number of bioinformatic approaches. They were then tested for their ability to promote export and translation of a reporter mRNA with a retained intron in conjunction with Rev or Rec. Some of the selected elements functioned well with either Rev, Rec or both, whereas some showed little or no function. Rev function on individual RcREs varied and was also dependent on the Rev sequence. We also performed RNAseq on total and cytoplasmic RNA isolated from SupT1 cells expressing HIV Rev, with or without Tat, or HERV-K Rec. Proviral mRNA from three HERV-K loci (4p16.1b, 22q11.23 and most significantly 3q12.3) accumulated in the cytoplasm in the presence of Rev or Tat and Rev, but not Rec. Consistent with this, the 3' RcRE from 3q12.3 functioned well with HIV-Rev in our reporter assay. In contrast, this RcRE showed little or no function with Rec. ConclusionsThe HIV Rev protein can functionally interact with many RcREs present in the human genome, depending on the RcRE sequence, as well as the Rev sequence. This leads to export of some of the HERV-K proviral mRNAs and also has the potential to change the expression of non-viral genes.

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“…Rec is a small RNA-binding protein considered to be a functional homolog of the HIV Rev accessory protein [13]. Rec contains a nuclear localization signal (NLS), which in addition to facilitating nuclear transport of the Rec protein, recognizes the Recresponsive element (RcRE) within the viral RNAs [14,18]. Binding of Rec to RcRE stabilizes incompletely spliced/unspliced viral transcripts and enhance their nuclear export [8,19,20] via the CRM1 export pathway [12,13,21].…”

Section: Introductionmentioning

confidence: 99%

Human Endogenous Retrovirus K Rec forms a regulatory loop with MITF that opposes the progression of melanoma to an invasive stage

Singh

Cai

Bunse

et al. 2020

Preprint

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In the human genome, HERV-K(HML2) is the most recently endogenized retrovirus 42 Through its interaction with CRM1 nuclear export factor [4, 6], Rec is involved in exporting un-43 spliced HERV-K RNA from the nucleus [3, 7]. In addition, Rec can directly modulate cell signalling 44 via binding to the promyelocytic leukemia zinc finger (PLZF) protein, a transcriptional repressor of 45 the c-MYC proto-oncogene [8]. Rec also binds the TZFP (testicular zinc-finger protein) and the hSGT 46 2 of 23 (human small glutamine-rich tetratricopeptide repeat protein), which are transcriptional repressors 47 of the androgen receptor [9, 10]. While it is evident that Rec must have first evolved to facilitate 48 HERV-K replication, there is speculation that the protein may have been coopted for physiological 49 function, such as spermatogenesis [6, 11] and defence against viral infections in the early human 50 embryo [12]. 51It has been reported that at least 18 HERV-K genomic loci can be transcribed in healthy human 52 tissues and express potentially-coding Rec or Np9 mRNAs (alone or in combination with retroviral 53 genes), though the landscape of transcribed HERV-K loci differs considerably between cell/tissue 54 types [13]. Rec RNA/protein expression has been observed in human embryonic tissues, placenta and 55 retina [14, 15]. Interestingly, HERV-K is expressed in both germinal-and pluripotent stem cells, 56 providing a special link between these cell types [16]. While HERV-K transcription has been observed 57 at low levels in various normal tissues, it is strongly induced upon environmental stress, such as 58 ultraviolet irradiation (e.g. UVB and UVC), starvation or viral infection that may manifest the global 59 DNA hypomethylation [17][18][19][20][21]. Furthermore, many studies have reported robust mRNA 60 upregulation of several genomic loci of HERV-K in various disease states, including certain 61 autoimmune diseases and a number of cancers, especially lung, breast cancers, germ cell tumours 62 and melanoma [18, 22, 23] and reviewed in [24, 25]. Moreover, transcriptional activation and 63 translation of various HERV-K products [22, 26] and even virus-like particles have been observed in 64 certain cancer cells such as teratoma, embryonic carcinoma and melanomas [3,[27][28][29]. 65Whether and how the overexpression of HERV-K products may contribute to the etiology or 66 progression of these diseases has been the subject of many studies, debates, and speculations. Several 67 mechanisms have been proposed by which HERV-K might contribute to disease. The activated LTRs 68 could act as alternative promoters and de-regulate tumor suppressor genes or proto-oncogenes 69 (reviewed in [35, 36]). Furthermore, the Env protein of HERV-K, via its fusogenic property, is capable 70 to induce cell-cell fusion and could therefore contribute to tumour invasiveness [18, 37, 38]. Env could 71 also have oncogenic properties through direct interference with cellular signalling pathways (e.g. 72RSS/MEK/ERK) [39, 40]. Indeed, the overexpressi...

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Biochemical Analysis of the Complex between the Tetrameric Export Adapter Protein Rec of HERV-K/HML-2 and the Responsive RNA Element RcRE pck30

Cited by 10 publications

References 47 publications

Human endogenous retrovirus-K (HML-2): a comprehensive review

Human endogenous retrovirus-K (HML-2): a comprehensive review

HIV-1 Rev interacts with HERV-K RcREs present in the human genome and promotes export of unspliced HERV-K proviral RNA

Human Endogenous Retrovirus K Rec forms a regulatory loop with MITF that opposes the progression of melanoma to an invasive stage

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