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Biochimie xxx (2015) 1e11

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Biochimie

journal homepage: www.elsevier .com/locate/biochi

Review

Infectious long non-coding RNAs

Konstantina Katsarou a, A.L.N. Rao b, Mina Tsagris c, Kriton Kalantidis a, c, *

a Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Crete, Greeceb Department of Plant Pathology and Microbiology, University of California, Riverside, CA, 92521-01222, USAc Department of Biology, University of Crete, Heraklion, Crete, Greece

a r t i c l e i n f o

Article history:Received 5 January 2015Accepted 7 May 2015Available online xxx

Keywords:ViroidsRNA satellitesHepatitis D viruslncRNA

* Corresponding author. Department of Biology, U2208, GR-71409, Heraklion, Crete, Greece.

E-mail address: kriton@imbb.forth.gr (K. Kalantidi

http://dx.doi.org/10.1016/j.biochi.2015.05.0050300-9084/© 2015 Published by Elsevier B.V.

Please cite this article in press as: K. Kaj.biochi.2015.05.005

a b s t r a c t

Long non protein coding RNAs (lncRNAs) constitute a large category of the RNA world, able to regulatedifferent biological processes. In this review we are focusing on infectious lncRNAs, their classification,pathogenesis and impact on the infected organisms. Here they are presented in two separate groups:‘dependent lncRNAs’ (comprising satellites RNA, Hepatitis D virus and lncRNAs of viral origin) whichneed a helper virus and ‘independent lncRNAs’ (viroids) that can self-replicate. Even though theselncRNA do not encode any protein, their structure and/or sequence comprise all the necessary infor-mation to drive specific interactions with host factors and regulate several cellular functions. These newdata that have emerged during the last few years concerning lncRNAs modify the way we understandmolecular biology's ‘central dogma’ and give new perspectives for applications and potential therapeuticstrategies.

© 2015 Published by Elsevier B.V.

1. Introduction

In 1956 Francis Crick developed the ‘central dogma’ ofmolecularbiology in which genetic information flows in a unidirectional wayfrom DNA to mRNA and then to protein [1]. However, in the pastthree decades distinct types of non protein coding RNAs (ncRNA) ofdifferent sizes and shapes have been reported making this land-marking theory incomplete to some extent. These ncRNAs havebeen implicated in regulation of different biological and physio-logical processes. Based on their size they can be separated intothree families: 1) short ncRNA (between 17 and 30 nt of length), 2)middle-size ncRNAs varying between 30 and 200 nt and finally 3)long ncRNAs (lncRNA), with RNAs over 200 nt (Fig. 1). lncRNAs mayactually be more important than initially thought. In fact, in theGENCODE 21 release of 2014, it is suggested that the humangenome contains at least 15.877 lncRNA genes and 9.534 shortncRNA genes (information in Ref. [2] and http://www.gencodegenes.org/). Their functional role remains mostly elusive,however there are cases implicating lncRNAs in gene expression (attranscriptional, post-transcriptional and epigenetic level) and thusnumerous cellular processes [3].

niversity of Crete, P.O. Box

s).

tsarou, et al., Infectious lo

Since the lncRNA field is relatively new, so far it has not beenclearly categorized, affecting results interpretation. lncRNAs can beseparated on the basis of their production pathway, way of action,overall structure, or influence on the organism (Fig. 1). Startingfrom the first, depending on their production it has been proposedto categorize lncRNAs as intergenic lncRNA, intronic lncRNA, senselncRNAs, antisense lncRNA and sense-overlapping lncRNA [3,4].Depending on their action they can be divided into cis-actinglncRNA controlling the expression of genes neighboring theirtranscription start site, or trans-acting lncRNA producing an acti-vation or repression of genes at distant loci (reviewed in Ref. [5]).They can also act as competing endogenous RNAs (ceRNA). Theseparticular lncRNAs are known as ‘miRNA sponges’ and their sug-gested role is to protect from degradation specific mRNAs, by tar-geting and sequestrating miRNAs, resulting in increase translationof these mRNAs [6]. lncRNAs can also be categorized by their shape,into linear (lincRNA) and circular (circRNA). The first group com-prises RNAs like ribosomal RNAs and RNAse P, important RNAs forproper cellular function. Endogenous circRNAs were reported forthe first time in HeLa cells in 1979, but at the time, were consideredas cryptic viral RNAs [7]. The first circRNA of exogenous origin wasviroid, whose circularity was confirmed by electron microscopy in1976 [8e10]. Till recently, circRNAs were considered to be a pecu-liarity of the viral world. However in recent years, with the adventof new sequencing technologies, numerous circRNAs have beendiscovered in several cells and tissues. Till today, 2000 circRNAs in

ng non-coding RNAs, Biochimie (2015), http://dx.doi.org/10.1016/

Fig. 1. Classification of long non-coding RNAs. Abbreviations: mRNA: messenger RNAs, ncRNA: non-coding RNA, miRNA: micro RNA, piRNA: piwi RNA, siRNA: small interfering RNA,tiRNA: transcription initiation RNA, crasiRNA: Centromere repeat associated small interacting RNA, telsRNAs: telomere-specific small RNA, tRNA: transfert RNA, snoRNA: smallnucleolar RNA, snRNA: small nuclear RNA, scRNA: small cytoplasmic RNA, cis-lncRNA: cis-acting long non coding RNA, trans-lncRNA: trans-acting long non coding RNA, ceRNA:competing endogenous RNA.

K. Katsarou et al. / Biochimie xxx (2015) 1e112

humans, 1900 in mice, 700 in nematodes, and a significant numberin other organisms have been identified, raising questions abouttheir biological significance [11e13].

Finally, we propose to divide lncRNAs into non-infectious andinfectious (Fig. 1). Infectious lncRNAs in their turn can be dividedinto non-replicative and replicative, since some of these lncRNAsare able to reproduce. This last category comprises infectious en-tities that can be separated into dependent and independent on thebasis of their ability to self-replicate (viroids) or use components ofa helper virus (satellite RNAs, HDV) for their infectivity. This reviewwill focus on infectious lncRNAs (viroids, satellite RNA, Hepatitis Dvirus) but also some lncRNAs of viral origin, and discuss importantaspects of their infectivity and common actions.

2. Independent infectious lncRNA

2.1. Viroids

- General aspects

Viroids are naked, circular, long non-coding RNA pathogens thatrange in size from 246 to 467 nt, causing plant diseases of economicimportance [14]. Theywere reported for the first time in 1971 in thespindle tuber disease of potato [8]. Since then, thirty-two differentviroid species have been identified and separated into two families(Pospiviroidae and Avsunviroidae) and eight genera (Avsunviroid,Pelamoviroid, Elaviroid for Avsunviroidae and Pospiviroid, Hostuvi-roid, Cocadviroid, Apscaviroid, Coleviroid for Pospiviroidae) [15,16].However, new viroids have been identified (ex. Dahlia latent viroid)and await approval by the International committee on taxonomy ofviruses (ICTV) [17]. Since their first discovery, viroid infections havebeen reported in every continent with different economic impactdepending on their host and the local phytosanitary measures

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[14,18]. In the 2014 quarantine pest list of the European and Med-iterranean plant protection organization (EPPO) there are threeviroids of the Pospiviroidae family present: Coconut cadangecadangviroid, Chrysanthemun stunt viroid and Potato spindle tuber viroid(PSTVd) and one, Tomato apical stunt viroid, in the alert list [19].

Viroid symptoms in host plants vary depending on theirgenomic RNA sequence/structure, the host and the environment.They range from mild to very severe, and affect either the entireplant or different organs such as leaves, fruits, flowers, roots andreserve organs [14]. Hosts are herbaceous, crop and woody plantspecies, as well as ornamentals [20,21]. Some of these hosts can actas reservoirs for potential future infections, imposing selectiveevolutionary pressure. The most recent example is the Potatospindle tuber viroid case (family: Pospiviroidae) which was foundmostly in asymptomatic ornamental plants (Solanaceae, Scrophu-lariaceae and Asteracae families) and nevertheless was able to infecttomato and potato [22,23]. However, viroid adaptation in thesehosts created minor sequence or structural changes that led todramatic effects on symptom expression [24e27].

Viroid spread is attributed to mechanical means and is facili-tated by harvesting and cultural operations. However, transmissionby seed, pollen, aphids and bumble bees have been proposed, withthe last two remaining controversial [28,29]. An additional trans-mission mode is plausible, since it has been proposed that upon co-infection of PSTVd with Potato leafroll virus (family: Luteoviridae,genus: Polerovirus) transencapsidation of the viroid is possible,transforming temporarily the viroid into a ‘virus’, facilitating itsspread and reducing the possibilities to control it [30,31].

- Molecular aspects

Pospiviroidae members, contain a rod-like or quasi rod-likesecondary structure with five distinct domains, C (central), P

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(pathogenic), V (variable), and two terminal domains (left-TL andright-TR). Their replication occurs in the nucleus via an asymmetricrolling circle mechanism [14,32e35]. Briefly, the circular (þ)RNA istranscribed into oligomeric (�)RNA, that is used as a template forthe synthesis of (þ)RNAs. Different proteins are involved, startingwith DNA-dependent RNA polymerase II complex (RNAP II). In-dications of its implication came early by Muhlbach and Sanger in1979, with the use of a-amanitin, a known inhibitor of the complex[36]. Direct proof came years later through binding assays and co-immunoprecipitation experiments implicating the TL viroiddomain [37e39]. However, since RNAPII is an enzyme composed ofmultiple subunits, additional studies are needed to fully under-stand the role of each unit in this process [33]. In order for theconcatemere to be cleaved into (þ)RNAs, the involvement of anRNase III enzyme has been proposed. In a recent publication DICER-

Table 1Host proteins interacting with infectious lncRNAs and lncRNAs of viral origin.

Family Type Host protein Ho

Viroids Pospiviroidae PSTVd VIRP1/BRP1 ?

RNAPII TraDNA ligase 1 DNeEIF1A TraTFIIIA TraL5 TraNt-4/1 ?

Histones Paint

CEVd eEIF1A TraRNAPII TraVIRP1/BRP1 ?

HSVd CsPP2 Train

VIRP1/BRP1 ?

Avsunviroidae PMLVd eEIF1A Trab-1,3-glucanase CeAminomethyltransferase enPutative chaperone ?Dynamin EnL5 Tra

ASBVd Phloem lectin PP2 Train

PARBP33 ChtRNA-ligase tRNCmmLec17 Tra

inSattelites Bromoviridae Q-satRNA VIRP1/BRP1 ?

Y-satRNA CHL1 ChPSV: satRNA rbcL; rbcS Ph

ATP synthetase enGLP Pla

HepatitisD virus

ADAR I RN

GADPH GlPKR TraRNAPI TraRNAPII TraRNAPIII TraPSF Pre

p54nrb PrehnRNPL PreASF PreeEF1A1 TraNUMA1 MiANKS6 ?FBXL-17 Ub

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Like protein 4 (DCL4), a known plant RNAse III protein, has beenshown to affect the accumulation of PSTVd in Nicotiana ben-thamiana (N.benthamiana), leaving open the question of a possibleeffect in the infectivity of PSTVd [40]. Finally, a ligase is necessary tocircularize this cleaved (þ)RNA into a fully functional molecule. In2012, DNA ligase 1 was proposed for the ligation redirecting a ‘DNAactivity’ into an ‘RNA activity’, another peculiarity of viroid biology[41]. It is to note that in earlier studies a tRNA ligase was showncapable of ligating PSTVd viroid monomers to circles [42], and aRNase alone was capable to circularize PSTVd monomers however,both were in vitro studies [43,44].

Avsunviroidae members, have a branched conformation with ahammerhead ribozyme structure that permit their self-cleavage,and replicate in chloroplasts via a symmetric rolling cycle mecha-nism [34,35,45]. This consists of a direct transcription of the circular

st function Proposed function forthe infectious agent

Reference

Nuclear import and/or systemic infection

[48e51]

nscription Replication [36,39]A ligation RNA ligation [41]nslation ? [62] a

nscription ? [63]nslation ? [63]

Implication in systemicmovement

[56,57]

ckaging of DNAo nucleosomes

? [59] a

nslation ? [64]nscription Replication [38]

Nuclear shuttling and/or systemic infection

[51] a

fficking of proteinsthe phloem

Long distance movement [53e55]

Nuclear shuttling and/or systemic infection

[50]

nslation ? [62]ll wall structure ? [62] a

zyme ? [62] a

? [62] a

docytosis ? [62] a

nslation ? [62]fficking of proteinsthe phloem

Long distance movement [61]

loroplastic transcription Acceleration of self cleavage [60]A loading Circularization [47]fficking of proteinsthe phloem

Long distance movement [61]

Nuclear import [96]lorophyll biosynthesis Yellow symptom phenotype [73,74]otosynthetic activity ? [103]zyme ? [103]nt growth and stress ? [103]A editing Post-transcriptional

modification of the antigenome[119]

ucose metabolism Enhances delta ribozyme activity [114]nslation Post-translational modification [130]nscription Antigenome synthesis [116]nscription Genome synthesis [114,115]nscription ? [116]-mRNA processing Recruitment of HDV

RNA to RNAPII[114]

-mRNA processing ? [114]-mRNA processing ? [114]-mRNA splicing ? [114]nslation ? [114]totic spindle stabilization ? [114] a

? [114] a

iquitin complex ? [114] a

(continued on next page)

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Table 1 (continued )

Family Type Host protein Host function Proposed function forthe infectious agent

Reference

KALRN-3 GEF protein ? [114] a

VirallncRNAS

Flaviviridae sfRNA (flavivirus) XMN1 50-30 exoribonuclease Production of the sfRNA [137]p100 Transcription and RNA transport Replication [142]Mov34 Transcription and Translation Replication [138]IF2B1 mRNA stability and translation ? [142]hnRNPQ Pre-mRNA processing ? [140]hnRNPA1 Pre-mRNA processing ? [140]hnRNPA2/B Pre-mRNA processing ? [140]PBMX Pre-mRNA processing ? [142]PTB Pre-mRNA processing Replication [139,142]EF1a Translation Replication [139]PABP Translation ? [141]La Translation Replication [139]YB-1 Translation Repression of viral

translation[140]

Retroviridae antisenselncRNA (Humanimmunodeficiencyvirus)

DNMT3a DNA methylation Transcriptional regulationof viral gene expression

[146]

Histones(H2A, H2B, H1)

Packaging of DNAinto nucleosomes

Transcriptional regulationof viral gene expression

[146]

Nucleolin Transcriptional activator Transcriptional regulationof viral gene expression

[146]

Nucleophosmin Ribosomal biogenesis andtransport of proteins tothe nucleolus

? [146]

RPL23a Translation ? [146] a

RPLP2 Translation ? [146] a

RRBP1 Translation ? [146] a

SRSF2 Pre-mRNA processing ? [146] a

Adenoviridae VA RNAI/VA RNAII

(Adenovirus)PKR Translation Inhibition of the repression

of translation[148]

La Translation Probable inhibition of therepression of translation

[149]

Dicer RNAi pathway Inhibition of miRNA biogenesis [151]Herpesviridae b2.7 (HCMV) GRIM-19 Mitochondrial complex I Protection from apoptosis [153]

EBER1/EBER2(Epstein-barr)

PKR Translation Inhibition of the repressionof translation

[155]

La Translation Probable inhibition of therepression of translation

[155]

L22 Tumorigenesis [155,167]hnRNPA1 Pre-mRNA processing ? [159]hnRNPA2/B1 Pre-mRNA processing ? [159]AUF1/hnRNPD Pre-mRNA processing Tumorigenesis [159]RIG-I Interferon activation [157]20-50 oligoadenylatesynthatase

RNA degradation pathway ? [156]

Nucleolin Transcriptional activator ? [158] a

PAN (Kaposi'ssarcoma virus)

Histones (H1, H2A) Packaging of DNA intonucleosomes

Nuclear scaffolding [168] a

SSBP1 Mitochondrial biogenesis Gene regulation [168] a

mtSSBP Mitochondrial biogenesis Gene regulation [168] a

IRF4 Transcription Increase of IL-4 production,alteration of immune responses

[168]

JMJD3 DNA Demethylation Gene expression [169] a

UTX DNA Demethylation Gene expression [169] a

MLL2 Histone methyl transferase Gene expression [169]SUZ12 Methylation Gene expression [170]EZH2 Methylation Gene expression [170]PABPC1 Translation and nuclear

RNA biogenesisModulation of PAN expression [163,164]

PABPC4 Translation ? [164]E1B-AP5/hnRNPUL1 Export of mRNAs Modulation of PAN expression [163]hnRNPC1 Pre-mRNA processing ? [171]

a Further experimental analysis is needed.

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(þ)RNA into a linear (�)RNA which will be auto-cleaved into unit-length molecules by the hammerhead ribozyme embedded in itsstructure and circularized to serve as a template for the generationof (þ)RNA, with exactly the same method. This process takes placein the chloroplasts where two different RNA polymerases exist:NEP (nuclear-encoded RNA polymerase) and PEP (plastid-encodedRNA polymerase). NEP is considered as the one involved in

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replication of ASBVd but a possible additional role for PEP can't beruled out [34,46]. The host enzyme mediating circularization ofboth (þ) and (�) RNA has recently been identified as the plantchloroplastic isoform of tRNA ligase [47].

Since viroids do not encode for any protein, their infection de-pends on their interaction with host protein (Table 1). In 2003,Martinez de Alba and colleagues identified a 65 kDa bromodomain-

ng non-coding RNAs, Biochimie (2015), http://dx.doi.org/10.1016/

K. Katsarou et al. / Biochimie xxx (2015) 1e11 5

containing protein (VIRP1/BRP1), comprising an RNA bindingdomain and putative nuclear localization signals (NLS) [48,49]. Thisprotein is capable of interacting with the TR domain of PSTVd andto a lower extend with HSVd [48e50]. RNAi N. benthamiana andN. tabaccum VIRP1-suppressed lines were incapable of infection byPSTVd or CEVd [51]. These results together with the nuclearlocalization of the protein suggest a possible role in viroid nuclearshuttling. However, an additional role in the replication and/or thesystemic viroid movement cannot be ruled out especially sinceearly work with PSTVd mutants showed that sequences in the TRbinding motif were found important for systemic trafficking [52].Another interesting case of a viroid-host protein interaction is thisof a very abundant phloem protein, containing an RNA bindingdomain, a 49 kDa lectin named PP2. This protein has been shown tointeract with different RNAmolecules, including HSVd (both in vitroand in vivo), and is thought to be implicated in the long distancemovement of viroids [53e55]. The recent discovery of a highlystructured 30 kDa protein, called Nt-4/1, capable of altering PSTVdaccumulation and/or movement [56,57] shows how complicatedthe analysis of host protein interaction with viroids is, especiallysince viroids have a high mutation rate which could potentiallyaffect their sequence and/or their structure [58]. It is to note thatdirect interaction of viroid with proteins such as histones, TFIIA andeIF1A has been shown [59e64] making the implication of viroids inchromatin regulation, transcription and translation a plausiblescenario.

Another important aspect in viroid-host protein interaction isthe indirect effects that viroid infection can have on host geneexpression which in turn could influence viroid infectious cycle.Introduction of new technologies such as microarrays and deepsequencing, have tremendously increased obtained data in thisarea. There are different studies proposing alteration in plant de-fense, stress response, hormone signaling, protein metabolism andin protein levels of specific cellular components such as chloro-plasts [65e68]. Of particular interest are kinase proteins intro-ducing cascade interactions and activating proteins and/orpromoters. One such is Protein Kinase RNA activated (PKR), where acorrelation between the pathogenicity of a strain and its ability ofphosphorylation have been demonstrated [69].

3. Dependent infectious lncRNA

3.1. Satellite RNAs

- General aspects

In 1977, the etiological agent for the lethal necrosis disease ofepidemic proportions among tomato plants in France was identi-fied to be a small, non-coding RNA found to be associated withCucumber mosaic virus (CMV-family: Bromoviridae, genus: Cucu-movirus) [70]. Since this small, non-coding RNA lacks the geneticinformation for coding any proteins, it hijacks the reproductivemachinery of the supporting helper virus (HV) for replication andencapsidation. Hence this subviral RNA pathogen is referred to as a“satellite” (sat-RNA)” [71]. The major differences between virusesand sat-RNAs are as follows. Unlike conventional viruses sat-RNAsare (i) incapable of self-replication and therefore dependent ontheir HVs for replication and encapsidation; (ii) lack of any recog-nizable sequence similarity with HV; (iii) usually interfere with HVreplication and finally (iv) modify symptom expression (eitherdecrease or increase) on the invading host plant [72e74].

Based on size and other properties, sat-RNAs are classified intothreemain groups: group 1, small-linear sat-RNAs (SL-sat-RNA); group2, long-linear sat-RNA (LL-sat-RNA) and group 3, circular sat-RNA (CR-sat-RNA). SL-sat-RNAs are shorter than 400 nt long. The sat-RNA of

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CMV is the classical example of a SL-sat-RNA. LL-sat-RNAs are usually0.7e1.5 kb and encode at least one nonstructural protein. sat-RNAassociated with Bamboo mosaic virus (family: Alphaflexiviridae,genus: Potexvirus) is the classical example of LL-sat-RNA. Finally, likeSL-sat-RNAs, CR-sat-RNAs are also shorter than 400 nt long exhibitingseveral features that are commonly shared with those of viroids.Therefore these CR-sat-RNAs are referred to as “virusoids” [75].

- Molecular aspects1. Enzymology of sat-RNA replication

Because of the inherent dependency of sat-RNAs associated withselective groups of taxonomically distinct plant viruses on theirrespective HVs, most replication studies have been performed in thepresence of HVs. In a given combination of a sat-RNA and its HV,replicase assays identified (i) that despite lack of recognizablesequence homology, HV replicase catalyzes the complete replicationof the sat-RNA [76e80] and (ii) how satRNA sequences maintain theintegrity of their 30 end during replication [81e84]. A hallmarkfeature of sat-RNA replication is the generation of multimers[85e88]. The mechanism regulating the generation of sat-RNAmultimers followed by the accumulation of monomeric forms var-ied between virus groups. For example, in nepo-and sobemoviruses,production of multimers is mediated through a rolling circlemechanism followed by accumulation of monomeric progeny as aresult of autocatalytic cleavage of the multimeric forms. This in-dicates that multimers in these satRNAs are intermediates[85,89,90]. By contrast, in sat-RNA of Turnip crinkle virus (family:Tombusviridae, genus: Carmovirus), generation of multimers wasimplicated to a mechanism involving re-initiation of replication byHV replicases before release of the nascent strand [86]. In sat-RNAsof CMV, it was hypothesized that dimeric forms are generated byself-ligation of double-stranded RNA monomers since no circularintermediates have been detected [91,92]. However, more recentevidence suggested that even in the absence of HV, a sat-RNA ofCMV can produce multimeric forms containing a hepta nucleotidemotif (HNM) at the junction due to host mediated transcription inthe nucleus; whereas a majority of multimers accumulated in thepresence of HV have a deletion of a 3’ terminal C-residue at thejunction [93]. Template independent addition of HNM at the junc-tion suggests that multimers formed in the absence of HV are notthe products of self-ligation. Additional mutations engineered toevaluate the significance of the multimers generated in the nucleusexemplified that the nuclear phase is functionally active and oblig-atory for HV-dependent replication [88].

Information obtained from cell biology approaches in conjunc-tion with transient expression of viral RNAs revealed that sat-RNAof CMV has propensity to localize in the nucleus both in the pres-ence and absence of its HV [93]. Since sat-RNA has no recognizableNLS, then the question that remains to be answeredwould be:whatmechanism regulates nuclear localization of sat-RNA? The subcellularsite of PSTVd replication is the nucleus and a bromodomain con-taining host protein (referred to as VRP1/BRP1) has been shown topromote nuclear import of PSTVd [48]. It is interesting to note thatthe replication of PSTVd was severely inhibited when the plantswere co-infected with CMV and its sat-RNA, whereas CMV alonehad no effect on the replication of PSTVd [94,95]. Since both PSTVdand sat-RNA have a nuclear phase in their replication cycles [93], itis reasonable to speculate that replication of PSTVd in co-infectedplants was abated by inhibiting PSTVd entry to the nucleus.These perceptions led to evaluate the likely role of VIRP1/BRP1 inthe nuclear importation of sat-RNA. Consequently, a series of cell-biology based assays in conjunction with confocal microscopyand transgenic N. benthamiana lines defective in VIRP1/BRP1expression clearly showed that nuclear import of sat-RNA is

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K. Katsarou et al. / Biochimie xxx (2015) 1e116

mediated by VIRP1/BRP1 [96]. Collectively these results suggestthat sat-RNA has two replication phases: a viroid-like and a virus-like replication phase.

Apart from sat-RNAs of CMV, SL-sat-RNAs associated with To-bacco ringspot virus (TobRSV-family: Secoviridae, subfamily:Comovirinae, genus: Nepovirus) and CR-sat-RNAs (virusoids) werealso studied extensively. Although the sat-RNA of TobSV is similarin size to that of CMV, it exhibits some features common to viroidsand virusoids, especially in replication. For example, during repli-cation in the presence of TobRSV, sat-RNA accumulates in multi-meric forms of (þ) and (�) polarity and (þ) and as well as (�)circular monomers [85]. Consequently, it was hypothesized that (þ)linear monomers are first circularized followed by transcription of(�)-multimers by a rolling circle mechanism [85]. These (�)-mul-timers are cleaved and circularized before being transcribed into(þ)-multimers that are subsequently cleaved to generate(þ)-monomers prior to encapsidation by HV capsid protein [76].Additional in vitro studies further revealed that both (þ) and(�)-monomers are generated by autocatalytic RNA processing ofmultimeric substrates [97]. Subsequent biochemical studies delin-eated that 'hammerhead' type ribozymes are involved in the pro-duction of (þ)-monomers, a feature that is commonly shared withvirusoids and viroids [75,76].

2. Molecular basis of sat-RNA pathogenesis

Prior to the development of recombinant DNA technology, mostof the studies performed with sat-RNAs were largely focused onsymptom expression and other (biochemical) aspects ofhostepathogen interactions. This is exemplified by early reports onthe effect that some strains of sat-RNAs have on the disease inducedby CMV. This is a complex relationship where the three genomes(plant, HV and satellite) interact. For example, one strain of sat-RNAof CMV was shown to change the classical “fern leaf' symptoms tonecrosis in tomato, but in all the other plants tested, symptomsremained either unchanged or were attenuated [70,98]. Similarly, asat-RNA from Japan that also induced necrosis on tomato modifiedthe symptoms on some species of Nicotiana from a mosaic to a bril-liant chlorosis [99], and yet another from North America completelymasked the symptoms of a CMV on tobacco that produced a brightyellow mosaic when inoculated in the absence of the satellite [100].With the advent of recombinant DNA technology, nucleotide se-quences responsible for host specificity disease induction weremapped [101,102]. For example, by testing the chimera between twoCMV sat-RNAs differing in their symptom phenotypes revealed thatinduction of a chlorosis phenotype in both tobacco and tomato iscontrolled by the same sequence domain; subsequent site-directedmutational analysis identified that a single nucleotide with in thisdomain changed the host plant specificity for a chlorotic response tosatellite RNA infection from tomato to tobacco. Recentmomentum inRNA silencing studies identified how sat-RNAs modify symptomexpression [72e74]. In addition, symptoms could eventually be aresponse to interaction of sat-RNA with host proteins. A recent pro-teomics study involving the sat-RNA of Peanut stunt virus (family:Bromoviridae, genus: Cucumovirus) identified several sat-RNAresponsive proteins such as carbohydrate, protein metabolism andstress-related factors [103]. However, the functionality of these hostproteins in the life cycle of sat-RNA remains to be validated.

3.2. Hepatitis D virus

- General aspects

At least five different hepatitis viruses have been identified andclassified into different families depending on specific

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characteristics. Hepatitis A virus belongs to Picornaviridae family,Hepatitis B virus (HBV), the only hepatic DNA virus, to Hep-adnaviridae, Hepatitis C virus to Flaviviridae, Hepatitis E virus toHepeviridae and finally Hepatitis D virus (HDV) is consider a delta-virus (ICTV release 2014). HDV is a defective satellite RNA viruswhich requires the helper function of HBV for its infectivity. Itsexistence was reported in 1977, but it was only in 1986 that it wasrecognized as a separate infectious agent [104,105]. There are about350 million HBV carriers in the world and among them around 15to 20 millions are co-infected with HDV, which is associated withthe more severe form of viral hepatitis [106]. Both HDV and HBVshare the same transmission routes which occurs either vertically(mother to child) or horizontally (person to person). There havebeen at least 8 genotypes identified (HDV1-8) [107].

- Molecular aspects

Even though HDV is considered a satellite virus, it containscharacteristics of an infectious long non-coding RNA similar toviroid. HDV possess a circular single stranded RNA of negativepolarity genome of 1679 nt (þ/�30 nt depending on the isolate). Itssequence comprises 74% base pairing, producing an unbranchedrod-like structure [108]. It does not encode its own replicase orRNA-dependent RNA polymerase to replicate its genome and isobliged to use host enzymes. HDV RNA encodes a ribozyme in orderto cleave its own RNA upon replication [109]. However, the struc-ture of the HDV ribozyme differs from the hammerhead RNAstructure observed in members of the Avsunviroidae family, andpresent homologies with a conservedmammalian ribozyme namedribozyme of the cytoplasmic polyadenylation element-binding pro-tein 3 gene (CPEB3). This observation increased speculation about apossible evolutionary connection of HDV with the human tran-scriptome [110]. Finally, it has been suggested that multimers ofHDV RNA are able to induce replication and spreading of the virusin leaves of tomato seedlings under certain conditions and on theother hand, PSTVd is able to replicate in hepatic cells expressingHDAg protein, proving that both share some infection features[111].

Replication occurs in the nucleus of hepatocytes via a double-rolling circle mechanism. Briefly, circular (þ)RNA become thetemplate for a linear, negative longer-than-unit RNAs which isselfcleaved by the ribozyme and finally ligated. In turn, this anti-genomic RNAwill become the template for (�)RNA which will alsobe self-cleaved and ligated (reviewed in Ref. [112]). It has beenshown that all three RNAPs are implicated. RNAPI is involved in thetranscription of the antigenome in the nucleoli, while RNAPII ca-talyses the replication from the antigenome in the nucleoplasm[113,114]. RNAPII interacts with the terminal stem-loop of HDVgenome of both polarities, exactly as it has been described for vi-roids [115]. Implication of RNAPIII has been proven but needsfurther elucidation [114,116].

During replication, a third population of RNAs with character-istics of an mRNA is produced (probably by RNAPII). This mRNAforms 7 open reading frames but only one seems to be functional[117]. This ORF is translated to a protein named S-HDAg (24 kDa). Apost transcriptional modification occurs by the adenosinedeaminase-1 (ADAR1) replacing the stop codon in position 196 bytryptophan codon, making possible the production of a 19 aminoacid bigger protein named L-HDAg (27 kDa) [112,118,119]. HDAgcontains an NLS signal, two RNA-binding domains, a cryptic RNA-binding domain in its N-terminus and a coiled-coil domain foroligomerization [120,121]. In L-HDAg a VAS (Virus ASsembly) and aNES (Nuclear Export Signal) motif are also observed [112,122]. HDAginteracts with HDV RNA to transport it to the nucleus for replication.After completion, it induces its export to the endoplasmic reticulum

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compartment for encapsidation [123,124]. Virions are sphericalchimeric structures of 36 nm diameter. The viral envelope consist ofHBV surface proteins whereas the inner ribonucleoproteic complexis made of HDV genomic RNA and 200 molecules of HDAg protein[125]. It is to note that HDV can also be encapsidated in the particleof another member of the Hepadnaviridae family, Woodchuck hep-atitis virus, which proves that the virus only use HBV as a ‘trans-portation vehicle’ for its infection [126].

HDV RNA interacts with host factors regulating cellular func-tions in order to enhance its infectivity [127]. This interaction maybe direct (Table 1) or indirect through its interaction with HDAg.HDAg undergo different post-translational modifications includingphosphorylation, acetylation, methylation, sumoylation and far-nesylation, permitting interactions with host proteins and thusregulation of viral infectivity [127]. An interesting example is theinteraction of HDAg with the transcription factor YY1 (Yin Yang 1)inducing association with the CBP/p300 complex (both bromodo-main proteins) and thereby enhancement of HDV replication [128].

Direct RNA-host protein interaction is also capable of influ-encing different steps of HDV life cycle. Glyceraldehyde 3-phosphate dehydrogenase (GADPH) is an enzyme normallyinvolved in glucose metabolism. However, its interaction with bothpolarities of HDV RNA induces nuclear translocation andenhancement of the ribozyme activity of the virus [114,129]. Itseems that upon HDV infection GADPH acts as a molecular chap-erone, unwinding viral RNA rendering the nascent viral RNA in aconformation with double pseudoknot structure and thusincreasing selfcleavage.

Another case of direct RNA-host protein interaction is that ofgenomic, antigenomic and subgenomic HDV RNAs with PKR, whichinduces its activation [130]. PKR is a kinase known to activatenumerous cellular factors including eIF2a, an important factor ofthe pre-initiation translation complex and plays important roles ininnate immunity. This interaction is rather peculiar since thisenzyme usually interacts with double stranded but not singlestranded RNA. However HDV RNA contains stretches of doublestranded helical regions which are most probably sufficient for theinteraction [131]. Nevertheless, this interaction, coupled with thatof eEF1A1 (Table 1), shows that HDV RNA is capable of modulatinghost translation.

3.3. Long non-coding RNAs of viral origin

- General aspects

Viruses contain limited genetic information packed into smallvirions, thus they have developed different methods for efficientutilization of this limited genetic code. For instance RNA virusesproduce subviral RNAs when they need to quickly translate a proteininto high yield (ex. CMV), or defective RNAs comprising importantdeletions when infection is persistent (ex. HCV) [132,133]. Anotherstrategy is the production of virus-encoded miRNA and lncRNAs.These RNAs do not replicate, since they are produced in only onepolarity. However, they do not encode any protein and seem to havedifferent roles depending on the nature of the infection [134]. Herewe will focus only on lncRNAs of viral origin.

- Molecular aspects1. RNA viruses

Flaviviriridae are monocictronic single-stranded (þ)RNA virusesinfecting humans and insects. In these viruses, the 50 UTR usuallycontains an IRES (Internal Ribosomal Entry Site) while 30UTR ahighly structured region with several stem loops [135]. Uponinfection a lncRNA is produced in several members of the flavivirus

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genus such as West Nile virus and Dengue virus. It has been termedas ‘subgenomic flavivirus RNA’ (sfRNA), sized between 300 and500 nt (reviewed in Ref. [136]). sfRNA is derived from an incom-plete degradation of genomic RNA by the cell 50-30 exoribonucleaseXRN1. This enzyme starts degrading viral RNA but stops when itreaches the 30UTRs structured region [136,137]. These lncRNAs havebeen proposed to interact with different host proteins includingproteins involved in transcription (p100, Mov34), splicing (PTB,hnRNPs) and translation (eIF1a, PABP, La) [136,138e142]. sfRNAfunction has not been fully elucidated, but there are indications thatit is involved in assisting the virus to escape the INF-a/b and RNAiresponses through i) interaction with cellular factors (Table 1) andii) production of siRNAs that will decoy RNAi components.

A similar 30UTR degradation intermediate that can act as alncRNA has also been described in Red clover necrotic mosaic virus(RCNMV), a plant virus of the Tombusviridae family. This viruscontains two RNAs. RNA1 encodes a RNA replicase and a proteinwith a RNA-dependent RNA polymerase motif. RNA2 encodes theviral movement protein. The coat protein is translated from asubgenomic RNA. In addition, a lncRNA of 400 nt is produced at the30UTR of RNA1, named SRf1. This lncRNA is encapsidated in thevirion and has been involved in the repression of the replicaseproduction which inhibits the creation of negative-strand RCNMVgenomic RNA [143]. A ‘degradation’ RNA product (proposed to actas a lncRNA) has also been described for the genus Benyvirus(Benyviridae family), Beet necrotic yellow vein virus. This lncRNA ofaround 500 nt named RNA3sub is not encapsidated and furtherinvestigations are necessary to clarify its role [144].

Another interesting RNA virus that has been proposed to pro-duce a viral lncRNA is Human immunodeficiency virus type-1 (fam-ily: Retroviridae, Subfamilly: Orthoretrovirinae). It consists of asingle-stranded, positive-sense, enveloped RNA virus, responsiblefor acquired immunodeficiency syndrome (AIDS) [145]. An impor-tant characteristic of HIV is the reverse transcription of its genomicRNA followed by integration into the host genome. Upon infection,apart from the canonical features, an antisense long non-codingRNA without a poly(A) tail has been recently discovered [146].The authors suggested nuclear retention of this lncRNA and inter-action with different nuclear factors (DNMT3a, nucleolin, nucleo-phosmin, histones, ribosomal proteins). They propose the followingmodel: Firstly, lncRNA recruits chromatin remodeling proteins andguide them to the viral promoter driving a transcriptional shut-down and thus an HIV latency period. Secondly, siRNAs producedby this same lncRNA by cellular factors (PTGS), could result in itsown repression, preventing the chromatic remodeling, leading toan activation of viral replication. Nevertheless, this is a ratherrecent theory and needs further investigation.

2. DNA viruses

lncRNAs in DNA viruses have been better studied than theircounterparts originating from RNA viruses, possibly because oftheir generally larger genome and their great abundance. The bestknown cases are members of Adenoviridae and Herspesviridae. Ad-enoviruses are non-enveloped DNA viruses (26-46 Kbp) associatedwith inflammations of respiratory, ocular and gastrointestinaltracts [147]. Upon infection, two highly structured cytoplasmicRNAs, named VA RNAI and VA RNAII (~170 nt), are produced fromRNAPIII. Different roles have been attributed to these lncRNAsbased on their ability to interact with different host proteins. Tostart, they are involved in viral translation. When infection occurs,interferon is produced by the organism, which in turns stimulatesproduction of PKR, known for its ability to bind dsRNA causing thephosphorylation of eIF2a, and thus blocking cellular translation ininfected cells. VA RNAI competes with dsRNA for PKR substrate,

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helping the virus to overcome this response to the infection [148].An additional ‘help’ to this mechanism comes from the action ofanother protein that interacts with both lncRNAs, LA antigen, thathas been proved to inhibit dsRNA-dependent activation of PKR, bybinding and unwinding dsRNA [149,150]. Another role for theselncRNAs, is their ability to decrease miRNA and siRNA biogenesis,firstly by inhibiting their cytoplasmic transport from exportin 5 andsecondly by interacting with Dicer protein, an important factor ofthe RNAi pathway, in both cases by direct competition [151].

Herpesviridae constitute an important familyof envelopeddouble-stranded linear DNA viruses (125e235 kbp) capable of producingdifferent diseases in animals. The characteristic of these viruses is thepersisting infection, with a long latency period and symptoms thatcan reappear numerous times in a patient lifetime [152]. Differentmembers of this family have been shown to produce lncRNA. Firstly,Human cytomegalovirus (subfamily: Betaherpesvirinae) at early stagesof infection, produces two very abundant (around 20% of total viraltranscription) lncRNA, of 1.2kband2.7 kb respectively.b2,7 is capableof binding GRIM-19 (genes associated with retinoid/interferon-induced mortality-19) a protein of the mitochondrial complex I,resulting in continued ATP production and protection from apoptosis[153]. Another member of this subfamily, Murine cytomegalovirushave also been found to produce a lncRNA of 7.2 kb (RNA7.2) but itsfunction is still under investigation [154]. EpsteineBarr (subfamily:Gammaherpesvirinae) produces two nuclear, highly structured andvery abundant lncRNAs, EBER1 and EBER2 (170 nt), transcribed byRNAPIII. These lncRNAs have been proposed to have different rolesbut probablymost of them result from interactionwith different hostfactors. Firstly, they interact with PKR and La, exactly as VA RNAs ofadenoviruses do,with same consequences for viral infection (detailedin Ref. [155]). Additional interaction of EBERs with proteins like L22,AUF1/hnRNPD, 20-50 oligoadenylate synthetase, RIG-I and nucleolinhave also been described but their exact role needs further elucida-tion [155e159]. In avery recentpublication,EBER2hasbeenproposedto indirectly recruit host transcription factor PAX5 on specific sites ofviral chromatin, proving themultitude of roles that lncRNAs can haveupon infection [160].

The most studied case of lncRNA by a DNAvirus is the extremelyabundant PAN RNA (Polyadenylated Nuclear RNA) of around 1.1 kbproduced by RNAPII, upon Kaposi's Sarcoma-associated Herpes-virus infection (KHSV- also known as Human Herpesvirus 8 -subfamily: Gammaherpesvirinae). PAN as its name indicates, has anuclear localization, is produced by RNAPII and is highly structured[161]. This lncRNA has been shown to interact with a great numberof host proteins (shown in Table 1) such as methylation, deme-thylation and transcription factors, which show an ability tointerfere with chromatin architecture and thus gene regulation. Inaddition, alteration at the translation level has been suggested, dueto the interaction with translation factor PABPC1 [162,163]. How-ever, this specific interaction has additional interesting features. Ithas been shown that upon the lytic phase of KHSV, the virus createsa hostile environment for host RNAs integrity. Polyadenylated PANlncRNAmanage to escape firstly, due to its abundance and secondlybecause of the relocation of PABPC1 protein in the nucleus, a pro-tein known to bind to poly (A) [162]. Apart from alteration of hostfactors, PAN is important also in the viral cycle. Specifically,knockdown of PAN with antisense oligos, decreases both virus lateaccumulation and infectious virion production [164].

4. Conclusion

For many years, lncRNAs were considered as transcriptional‘noise’. The only exceptions were infectious lncRNA, viroids and sat-ellite RNAs, for which studies started in the 70's. These infectiousagents are responsible for important diseases around the world, in

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differentorganismsoftenwithhigheconomic impact. In the last yearsa great number of host and pathogens related lncRNA has beendiscovered inmany organisms, with their role remaining elusive. It isinteresting that evenviruses thathave a completemachinery for theirviral cycle and therefore do not have an apparent need for additionalcomponents, produce lncRNA upon infection. These lncRNAs, eventhough they differ in many ways, share common features.

All infectious lncRNA (dependent and independent) seem to behighly structured, enriched in conserve nucleotides, with increasedself complementarity and presence of important stem loops. Vi-roids, sat-RNA and HDV are replicating through variations of therolling cycle mechanism, by RNAPII. Most of lncRNAs of viral originare also using RNAPII for their production with the exception of VARNAI and VA RNAII which are produced by RNAPIII, and sfRNA/RNA3sub which constitute degradation products. Viroids, satelliteRNAs, HDV, SRf1, RNA3sub can be trans-encapsidated into virionsindicating that their structure contains all the necessary elementsfor this, as well as their importance in the infection processes.

All lncRNA described in this review have a direct or indirectimpact in gene regulation, and often affect important cellularfunctions. Specifically, (i) lncRNA from viroids, HDV and HIV, havebeen proved to interact with histones and/or cellular bromodomainproteins (VIRP1/BRP1, p300, CBP). PAN has also been found tointeract with methylation and demethylation factors. Takentogether, these results show a possible role of these lncRNAs inmodification of chromatin architecture. (ii) Interactions withimportant transcription factors and factors of the splicing ma-chinery (RNAPI,II,III, GADPH, TFIIIA, hnRNP, PSF, etc) show apossible involvement of these lncRNA in transcription regulationand/or quality of the produced transcripts. (iii) Interaction withfactors of the translation complexes such as eIFA1, PABP and ribo-somal proteins, show a possible implication in protein production.(iv) Infectious lncRNA and lncRNAs of viral origin, have been shownto interact with proteins capable of producing signaling cascadesthrough phosphorylation, one such is PKR. Upon infection PKR isresponsible for viral RNA recognition and interferon (IFN) pathwayactivation. However, PKR can also alter translation including INFmRNA translation, and has also been shown to activateMAPKs suchas JNK and p38 [165]. (v) The interaction of these lncRNAs with cellhost factors could eventually fool the antiviral defense of the or-ganism by making them less immunogenic.

An additional point of convergence between the presentedlncRNA is the fact that they are targeted by cellular RNAi compo-nents. This is shown either by direct interactionwith Dicer proteins(VA RNAI) and/or by the production of small RNAs. It is reasonableto propose that these lncRNAs could eventually act as a sort ofceRNAs in order to overflow the cellular defense system.

Upon different kind of infections or diseases, endogenous lncRNAcan be produced and are responsible for the fast development of therespective disease [166]. The disease relevance of ncRNAs is likely togenerate a great deal of excitement in the near future. Understandingthe molecular and pathogenic interactions of infectious lncRNAs willbring knowledge that will change the perspectives of RNA regulatedphenomena, but could also eventually provide a source for thedesigning of new therapeutic strategies for several importantdiseases.

Conflict of interest

We declare that there is no conflict of interest.

Acknowledgments

Viroid and virus research in Dr. K. Kalantidis lab is supported bythe Greek ‘Ministry of education and life-long learning’ through

ng non-coding RNAs, Biochimie (2015), http://dx.doi.org/10.1016/

K. Katsarou et al. / Biochimie xxx (2015) 1e11 9

two NSRF/ESPA grants (Aristeia II-4499 and Synergasia09SYN_22_638 for viroids and viruses respectively), research in Dr.A.L.N. Rao lab is supported by a grant from UCR Academic Senate(A01863) and RSAP (19900NWAR).

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