Flavivirus 3' UTR

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Flavivirus 3' UTR are untranslated regions in the genome of viruses in the genus Flavivirus .

Contents

Background

The Flavivirus positive-oriented, single-stranded RNA genome has a length of 10,000 - 11,000 bases. The genus includes human pathogens like Zika virus, West-Nile virus, Dengue virus, Yellow Fever virus and other. [1]

The 3' UTR ranges between 400 and 700 nucleotides in length. [2] Its RNA secondary structure is known to be necessary for the viral replication during infection. In contrast to the structurally conserved 5' UTR of flaviviruses, individual structural elements differ between different viruses, which is associated with the host-adaptation. Flaviviruses are therefore classified into four different groups: Mosquito-borne flaviviruses (MBFV), tick-borne flaviviruses (TBFV), insect-specific flaviviruses (ISFV) and those with no known vector (NKV). [3] [4]

Across all groups, three RNA secondary structure elements are conserved within the 3' UTR: the dumbbell element (DB), cis-acting replication element (CRE) and the exoribonuclease-resistant RNA elements (xrRNA). Further, unique elements have been observed for specific groups as well.[ citation needed ]

Subgenomic flavivirus RNA

The 3' UTR of flavivirus - and sometimes even a small part of the 3' end of the coding region - is also called subgenomic flavivirus RNA (sfRNA). [5] It has been shown that sfRNA is implied in many different pathways that comprises both, host defenses and viral infection. [6] [7] [8] SfRNA is produced by incomplete degradation of the viral genome by the host cell (via XRN1). [9] Local RNA secondary structures (xrRNA elements) in the 3' UTR and long-range RNA-RNA interactions between 5' UTR and 3' UTR of flaviviruses stall XRN1 and causes the undigested fragment of the genome.[ citation needed ]

xrRNA element

The exoribonuclease-resistant RNA elements (xrRNA) are described throughout all groups of flaviviruses. Usually, each virus harbors two xrRNAs, xrRNA1 and xrRNA2, in the beginning of the 3' UTR. [10] The formation of these stem-loops, especially xrRNA1, is vital to ensure resistance against XRN1 activity. [11] The Y-shaped stem-loop is also termed SL II and SL IV, respectively. In order to function as xrRNA, the sequence downstream is needed as well, since the upper loop region forms a pseudoknot (PK) with the single-stranded region directly downstream to its respective hairpin. In some species, the region downstream also forms a small hairpin. In such cases, the PK interactions takes place between the two loop regions. Conserved formation of these structures were observed in mammalian cells but not in mosquito cells, suggesting this region has varying functions in different hosts. [12] [13] In plant-viruses, xrRNA elements have been observed as well, showing some similarities to flaviviral xrRNAs. [14] [15] However, plant-virus xrRNA and flaviviral xrRNA are distinguishable by their underlying three-dimensional folds. [16] It has been reported that xrRNAs block the progression of 5' to 3' exoribonuclease producing subgenomic RNAs. [3] xrRNA elements can be found in some of the deadliest viruses in agriculture including, potato leafroll virus (PLRV), leading responsible virus for worldwide potato yield loss, [5] maize chlorotic mottle virus (MCMV), responsible for 90% maize/corn yield loss in sub-Saharan Africa, [6] and maize yellow dwarf virus-RMV (MYDV- RMV), formerly BYDV-RMV. [7]

Dumbbell element

The dumbbell element (DB) are important for viral RNA synthesis. [17] Via the formation of additional pseudoknots, the loop regions of DB pairs with a complementary motif further downstream of the respective DB element. [18] [19] The DB elements also expose conserved sequences (CS) and repeated conserved sequences (RCS). [20] Further, the DB elements are also playing a role in viral translation, as deletion of both elements reduced viral translation levels. [21] [22]

Pseudoknot-forming stem-loops

There is evidence that pseudoknot-forming stem-loops (SL-PK) are encoded by dual-host insect-specific flaviviruses and classical insect-specific flaviviruses [23] but while short stem-loops are present in the genomes of all mosquito-borne flaviviruses, they are not involved in pseudoknot interactions for which structural is available. [24] [25] It is thought that SL-PK might stabilise xrRNAs or confer additional XRN1 resistance as abolishing the SL-PK of various viruses reduces the production of sfRNAs. [23]

CRE structure

The cis-acting replication element (CRE) structure is structurally conserved among known flaviviruses. It consists of a small hairpin (sHP) and a larger structural element (3'SL). Mutations of sHP are shown to be lethal for Dengue virus in mosquito cells. [26] CRE is highly involved in the 5'-3' UTR interaction of flaviviruses. [27] Regions of sHP are interacting with the SLB element and the cHP in the 5' UTR, whereas the 3'SL harbors a sequence that can interact with SLB, to further stabilize this long-range RNA-RNA interaction.

Repeated elements

In ISFV, structural alignments of the 3' UTR revealed that many species harbor three to four repeats of two highly conserved elements, termed Ra and Rb. [28] [29] These elements show variable loop regions and low sequence conservation in the Ra element. However, strong structure conservation and the occurrence of multiple copies may hint towards a possible functional importance of these elements. [29]

SL6 short hairpin

In different studies, a short stem-loop, named SL6 has been observed in at least TBEV, LGTV and OHFV. [30] [31] SL6 shows a high heterogeneity among different tick-borne flaviviruses, but is structurally conserved supported by multiple covariation. [29]

Related Research Articles

<i>Flaviviridae</i> Family of viruses

Flaviviridae is a family of enveloped positive-strand RNA viruses which mainly infect mammals and birds. They are primarily spread through arthropod vectors. The family gets its name from the yellow fever virus; flavus is Latin for "yellow", and yellow fever in turn was named because of its propensity to cause jaundice in victims. There are 89 species in the family divided among four genera. Diseases associated with the group include: hepatitis (hepaciviruses), hemorrhagic syndromes, fatal mucosal disease (pestiviruses), hemorrhagic fever, encephalitis, and the birth defect microcephaly (flaviviruses).

<i>Flavivirus</i> Genus of viruses

Flavivirus, renamed Orthoflavivirus in 2023, is a genus of positive-strand RNA viruses in the family Flaviviridae. The genus includes the West Nile virus, dengue virus, tick-borne encephalitis virus, yellow fever virus, Zika virus and several other viruses which may cause encephalitis, as well as insect-specific flaviviruses (ISFs) such as cell fusing agent virus (CFAV), Palm Creek virus (PCV), and Parramatta River virus (PaRV). While dual-host flaviviruses can infect vertebrates as well as arthropods, insect-specific flaviviruses are restricted to their competent arthropods. The means by which flaviviruses establish persistent infection in their competent vectors and cause disease in humans depends upon several virus-host interactions, including the intricate interplay between flavivirus-encoded immune antagonists and the host antiviral innate immune effector molecules.

<i>Nidovirales</i> Order of positive-sense, single-stranded RNA viruses

Nidovirales is an order of enveloped, positive-strand RNA viruses which infect vertebrates and invertebrates. Host organisms include mammals, birds, reptiles, amphibians, fish, arthropods, molluscs, and helminths. The order includes the families Coronaviridae, Arteriviridae, Roniviridae, and Mesoniviridae.

<span class="mw-page-title-main">Coronavirus 3′ stem-loop II-like motif (s2m)</span> Genetic motif present in some viruses

The Coronavirus 3′ stem-loop II-like motif is a secondary structure motif identified in the 3′ untranslated region (3′UTR) of astrovirus, coronavirus and equine rhinovirus genomes. Its function is unknown, but various viral 3′ UTR regions have been found to play roles in viral replication and packaging.

<span class="mw-page-title-main">Coronavirus 3′ UTR pseudoknot</span>

The Coronavirus 3′ UTR pseudoknot is an RNA structure found in the coronavirus genome. Coronaviruses contain 30 kb single-stranded positive-sense RNA genomes. The 3′ UTR region of these coronavirus genomes contains a conserved ~55 nucleotide pseudoknot structure which is necessary for viral genome replication. The mechanism of cis-regulation is unclear, but this element is postulated to function in the plus-strand.

<span class="mw-page-title-main">Coronavirus packaging signal</span> Regulartory element in coronaviruses

The Coronavirus packaging signal is a conserved cis-regulatory element found in Betacoronavirus. It has an important role in regulating the packaging of the viral genome into the capsid. As part of the viral life cycle, within the infected cell, the viral genome becomes associated with viral proteins and assembles into new infective progeny viruses. This process is called packaging and is vital for viral replication.

<span class="mw-page-title-main">R2 RNA element</span>

The R2 RNA element is a non-long terminal repeat (non-LTR) retrotransposable element that inserts at a specific site in the 28S ribosomal RNA (rRNA) genes of most insect genomes. In order to insert itself into the genome, retrotransposon encoded protein (R2) protein makes a specific nick in one of the DNA strands at the insertion site and uses the 3′ hydroxyl group exposed by this nick to prime the reverse transcription process termed target primed reverse transcription (TPRT), where the RNA genome is transcribed into DNA.

<span class="mw-page-title-main">Tombusvirus 3′ UTR region IV</span>

Tombusvirus 3′ UTR is an important cis-regulatory region of the Tombus virus genome.

<span class="mw-page-title-main">Tombusvirus 5′ UTR</span>

Tombusvirus 5′ UTR is an important cis-regulatory region of the Tombus virus genome.

<span class="mw-page-title-main">Red clover necrotic mosaic virus translation enhancer elements</span>

Red clover necrotic mosaic virus (RCNMV) contains several structural elements present within the 3′ and 5′ untranslated regions (UTR) of the genome that enhance translation. In eukaryotes transcription is a prerequisite for translation. During transcription the pre-mRNA transcript is processes where a 5′ cap is attached onto mRNA and this 5′ cap allows for ribosome assembly onto the mRNA as it acts as a binding site for the eukaryotic initiation factor eIF4F. Once eIF4F is bound to the mRNA this protein complex interacts with the poly(A) binding protein which is present within the 3′ UTR and results in mRNA circularization. This multiprotein-mRNA complex then recruits the ribosome subunits and scans the mRNA until it reaches the start codon. Transcription of viral genomes differs from eukaryotes as viral genomes produce mRNA transcripts that lack a 5’ cap site. Despite lacking a cap site viral genes contain a structural element within the 5’ UTR known as an internal ribosome entry site (IRES). IRES is a structural element that recruits the 40s ribosome subunit to the mRNA within close proximity of the start codon.

Spondweni virus is an arbovirus, or arthropod-borne virus, which is a member of the family Flaviviridae and the genus Flavivirus. It is part of the Spondweni serogroup which consists of the Sponweni virus and the Zika virus (ZIKV). The Spondweni virus was first isolated in Nigeria in 1952, and ever since, SPONV transmission and activity have been reported throughout Africa. Its primary vector of transmission is the sylvatic mosquito Aedes circumluteolus, though it has been isolated from several different types of mosquito. Transmission of the virus into humans can lead to a viral infection known as Spondweni fever, with symptoms ranging from headache and nausea to myalgia and arthralgia. However, as SPONV is phylogenetically close to the ZIKV, it is commonly misdiagnosed as ZIKV along with other viral illnesses.

<i>West Nile virus</i> Species of flavivirus causing West Nile fever

West Nile virus (WNV) is a single-stranded RNA virus that causes West Nile fever. It is a member of the family Flaviviridae, from the genus Flavivirus, which also contains the Zika virus, dengue virus, and yellow fever virus. The virus is primarily transmitted by mosquitoes, mostly species of Culex. The primary hosts of WNV are birds, so that the virus remains within a "bird–mosquito–bird" transmission cycle. The virus is genetically related to the Japanese encephalitis family of viruses. Humans and horses both exhibit disease symptoms from the virus, and symptoms rarely occur in other animals.

Parramatta River virus (PaRV) is an insect virus belonging to Flaviviridae and endemic to Australia. It was discovered in 2015. The virus was identified from the mosquito Aedes vigilax collected from Sydney under the joint research project by scientists at the University of Queensland and the University of Sydney. In experimental infections, the virus is unable to grow in vertebrate cells, but only in Aedes-derived mosquito cell lines. This suggests that the virus does not infect vertebrates. The name is given because it was discovered from Silverwater, a suburb of Sydney on the southern bank of the Parramatta River. The mosquitoes from which the virus was isolated were actually collected in 2007, and had been preserved since then. The study commenced only after the development of the technique of viral detection in mosquitoes in the University of Queensland.

<span class="mw-page-title-main">Palm Creek virus</span> Species of virus

Palm Creek virus (PCV) is an insect virus belonging to the genus Flavivirus, of the family Flaviviridae. It was discovered in 2013 from the mosquito Coquillettidia xanthogaster. The female mosquitoes were originally collected in 2010 from Darwin, Katherine, Alice Springs, Alyangula, Groote Eylandt, Jabiru and the McArthur River Mine, and had since been preserved. The discovery was made by biologists at the University of Queensland. The virus is named after Palm Creek, near Darwin, from where it was originally isolated.

Yokose virus (YOKV) is in the genus Flavivirus of the family Flaviviridae. Flaviviridae are often found in arthropods, such as mosquitoes and ticks, and may also infect humans. The genus Flavivirus includes over 50 known viruses, including Yellow Fever, West Nile Virus, Zika Virus, and Japanese Encephalitis. Yokose virus is a new member of the Flavivirus family that has only been identified in a few bat species. Bats have been associated with several emerging zoonotic diseases such as Ebola and SARS.

<i>Sepik virus</i> Mosquito transmitted virus endemic to Papua New Guinea

Sepik virus (SEPV) is an arthropod-borne virus (arbovirus) of the genus Flavivirus and family Flaviviridae. Flaviviridae is one of the most well characterized viral families, as it contains many well-known viruses that cause diseases that have become very prevalent in the world, like Dengue virus. The genus Flavivirus is one of the largest viral genera and encompasses over 50 viral species, including tick and mosquito borne viruses like Yellow fever virus and West Nile virus. Sepik virus is much less well known and has not been as well-classified as other viruses because it has not been known of for very long. Sepik virus was first isolated in 1966 from the mosquito Mansoniaseptempunctata, and it derives its name from the Sepik River area in Papua New Guinea, where it was first found. The geographic range of Sepik virus is limited to Papua New Guinea, due to its isolation.

<i>Modoc virus</i> Species of virus

Modoc virus (MODV) is a rodent-associated flavivirus. Small and enveloped, MODV contains positive single-stranded RNA. Taxonomically, MODV is part of the Flavivirus genus and Flaviviridae family. The Flavivirus genus includes nearly 80 viruses, both vector-borne and no known vector (NKV) species. Known flavivirus vector-borne viruses include Dengue virus, Yellow Fever virus, tick-borne encephalitis virus, and West Nile virus.

Coronavirus genomes are positive-sense single-stranded RNA molecules with an untranslated region (UTR) at the 5′ end which is called the 5′ UTR. The 5′ UTR is responsible for important biological functions, such as viral replication, transcription and packaging. The 5′ UTR has a conserved RNA secondary structure but different Coronavirus genera have different structural features described below.

Coronavirus genomes are positive-sense single-stranded RNA molecules with an untranslated region (UTR) at the 3′ end which is called the 3′ UTR. The 3′ UTR is responsible for important biological functions, such as viral replication. The 3′ UTR has a conserved RNA secondary structure but different Coronavirus genera have different structural features described below.

<span class="mw-page-title-main">Flavivirus 5' UTR</span> Untranslated regions in the genome of viruses in the genus Flavivirus

Flavivirus 5' UTR are untranslated regions in the genome of viruses in the genus Flavivirus.

References

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