HIV Rev response element

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The HIV-1 Rev response element (RRE) is a highly structured, ~350 nucleotide RNA segment present in the Env coding region of unspliced and partially spliced viral mRNAs. In the presence of the HIV-1 accessory protein Rev, HIV-1 mRNAs that contain the RRE can be exported from the nucleus to the cytoplasm for downstream events such as translation and virion packaging. [1] [2]

Contents

RRE Location in the HIV-1 Genome. RRE is located within the Env coding region of HIV-1. HIV Genome Org wRRE.png
RRE Location in the HIV-1 Genome. RRE is located within the Env coding region of HIV-1.

RRE and HIV-1 biology

Early phase

HIV-1 RNA export. In the early phase (top), transcribed viral RNAs (9kb) are spliced down to 2kb before export. One of these 2kb messages is translated to produce Rev which is then imported into the nucleus. In the late phase (bottom), Rev binds the RRE of newly transcribed RNAs before splicing and exports the unspliced (9kb) and partially spliced (4kb) messages to the cytoplasm. Translation of these messages produces late stage viral proteins. 9 kb messages can also serve as genomes for new virions. HIV REV RRE FUNCTION.png
HIV-1 RNA export. In the early phase (top), transcribed viral RNAs (9kb) are spliced down to 2kb before export. One of these 2kb messages is translated to produce Rev which is then imported into the nucleus. In the late phase (bottom), Rev binds the RRE of newly transcribed RNAs before splicing and exports the unspliced (9kb) and partially spliced (4kb) messages to the cytoplasm. Translation of these messages produces late stage viral proteins. 9 kb messages can also serve as genomes for new virions.

The HIV-1 genome contains a single promoter and uses multiple reading frames and alternative splicing to encode 15 proteins from a single pre-mRNA species. [3] Transcription from an integrated HIV-1 provirus generates a single 9 kilobase (kb) pre-mRNA containing multiple splice sites and nuclear retention signals. In the early phase of the viral life cycle, this pre-RNA is completely spliced to RRE-free, 2 kb messages. These smaller messages are then transported from the nucleus to the cytoplasm via standard mRNA nuclear export pathways [4] (see Figure). One of these small, 2kb messages encodes the HIV-1 Rev protein which is imported into the nucleus via its nuclear localization sequence. This phase of the virus life cycle is both Rev and RRE independent. [2]

Late phase

The late phase of the viral life cycle is characterized by the expression of viral proteins that are encoded on the long, unspliced (9kb) or partially spliced (4 kb) messages containing the RRE. Because of their retention and splicing signals, these intron-containing RNAs are initially retained in the nucleus for splicing/degradation. However, after a sufficient level of Rev has been produced by the 2 kb messages, these longer messages can be exported to the cytoplasm via a Rev dependent export pathway. Nuclear export of these RNAs is achieved by a specific, co-operative assembly of multiple Rev molecules on the RRE. Assembly of this Rev-RRE complex is followed by the recruitment of a human protein complex containing the proteins exportin-1 (XPO1/CRM1) and Ran-GTP. Rev recruits this export machinery via a nuclear export sequence (NES) present in Rev. This Rev-RRE-Xpo1/RanGTP complex is then transported to the cytoplasm. In the cytoplasm, these messages are translated to produce all the remaining viral proteins or packaged as genomes for newly budding virions (see Figure). [2]

Secondary Structure and Rev Recognition

The RRE is a highly structured RNA element. Computational predictions, later verified by chemical and enzymatic probing, indicate that RRE contains multiple stem loops and bulges (see Figure). Rev binds to RRE in a sequence specific manner with Rev-RNA recognition mediated by a 17-residue a-helical stretch on Rev, the Arginine-Rich-Motif (ARM).

RRE Secondary Structure. Secondary Structure of the minimal functional RRE (~250 nt). The RRE contains several stem loops, the most well characterized being the high affinity binding site, IIB. IIB is necessary but not sufficient for RRE mediated export. Stem IA is a more recently identified, secondary binding site. The remaining binding sites on the RRE have not been characterized yet. HIVRRE SecondaryStructure.png
RRE Secondary Structure. Secondary Structure of the minimal functional RRE (~250 nt). The RRE contains several stem loops, the most well characterized being the high affinity binding site, IIB. IIB is necessary but not sufficient for RRE mediated export. Stem IA is a more recently identified, secondary binding site. The remaining binding sites on the RRE have not been characterized yet.

Stem IIB: a high-affinity binding site

Stem IIB is a site on the RRE which Rev binds with high affinity and specificity. The structure of an isolated stem IIB bound to a peptide corresponding to a Rev-ARM has been solved by NMR. [5] This structure reveals an RNA A-form major groove widened by purine-purine base pairs at the purine-rich bulge to accommodate the a-helical Rev-ARM. Binding is achieved through a combination of base-specific contacts and electrostatic contacts with the phosphate backbone (see figure). More recent studies have identified another region on the RRE, stem IA, that binds Rev in a specific manner, but with a 5-fold weaker affinity than stem IIB. [6]

Rev-ARM/IIB structure. (Left) Stem IIB RNA(red) A--form major groove cradling the Rev--ARM a--helix (blue). The Rev-ARM is a short peptide that represents the RNA binding domain of Rev. (Right) A rotated view showing the purine--purine base pairs (yellow) that widen the RNA major groove. HIV IIBRRE REV17.png
Rev-ARM/IIB structure. (Left) Stem IIB RNA(red) A-‐form major groove cradling the Rev-‐ARM α-‐helix (blue). The Rev-ARM is a short peptide that represents the RNA binding domain of Rev. (Right) A rotated view showing the purine-‐purine base pairs (yellow) that widen the RNA major groove.

Co-operative Rev assembly required for RRE function

Although Stems IIB and IA can bind Rev in isolation, a full-length RRE (at least ~250 nt) is required for viral function. Multiple molecules of Rev bind to the full RRE in a specific and co-operative manner through a combination of Rev-RNA and Rev-Rev interactions. [6] [7] [8] It is believed that IIB acts as an "anchor point", with the Rev molecules bound at secondary sites (such as IA) stabilized by protein-protein interactions with other Rev molecules (in addition to the RNA-protein interactions). Biochemical studies on a 242-nucleotide RRE have established a ratio of 6 Rev monomers to each RRE. [9]

In a sense, the RRE acts as a scaffolding platform onto which a specific and co-operative complex of Revs (and eventually cellular export machinery) assembles. This cooperativity that is dictated by RRE structure and sequence is required for the formation of a high affinity, export-competent complex. [10] Current models of Rev assembly on the RRE suggest an initial Rev nucleation event at stem IIB followed by progressive addition of Rev molecules to form the full complex. [7] [8] [11] [12]

Rev-RRE Complexes recruit additional partners

After assembly of a Rev-RRE complex, cellular export machinery must be added to guide the RNA through the nuclear pore. Nuclear export of Rev-RRE containing mRNAs is achieved using the human Crm1-RanGTP nuclear export pathway. Rev contains a nuclear export sequence (NES) that binds Crm1, [13] [14] and Crm1 guides the entire complex out of the nucleus.

Recent crystal structures of Rev, [15] [16] the Rev-ARM/Stem IIB structure and the information on Rev-RRE stoichiometry have led to the proposal of a jelly-fish model for a functionally active complex. In this model, The RRE provides a structural scaffold to assemble a Rev hexamer, and this assembly forms the head of the jelly-fish. The NESs from the 6 Rev monomers form the jelly-fish "tentacles" that could interact with the host Crm1-RanGTP proteins. [15] This entire "jellyfish" would then be exported to the cytoplasm (see Figure).

Jellyfish model of Rev/RRE assembly. This is a schematic representation of how an export-competent Rev-RRE complex might form: Rev molecules assemble onto the RRE scaffold to form an oligomeric assembly. In the "jellyfish" model, the jellyfish head comprises Rev oligomers and RRE; the Rev-NESs form the "tentacles" that interact with Crm1 (shown in the space-filled model) making the complex ready for export. HIV REV RRE JELLYFISH.png
Jellyfish model of Rev/RRE assembly. This is a schematic representation of how an export-competent Rev–RRE complex might form: Rev molecules assemble onto the RRE scaffold to form an oligomeric assembly. In the “jellyfish” model, the jellyfish head comprises Rev oligomers and RRE; the Rev–NESs form the "tentacles" that interact with Crm1 (shown in the space-filled model) making the complex ready for export.

Tertiary structure

Images of the tertiary structure of RRE (and the Rev-RRE complex) have been captured using atomic force microscopy. [17] These images show a globular "head" with a long stalk extending from it and are in accordance with 3D predictions from computer models, as well as electron microscope (EM) images of assembled Rev-RRE complexes. [15]

Rev-RRE as a Drug Target

As the export of RRE-containing RNAs is essential for HIV replication, the association of RRE and Rev is an attractive therapeutic target. [18] Various RNA cleavage methods and small molecule screens [19] have been implemented in an effort to design antiviral drugs to treat HIV infection. [18] [20] Rev and RRE are particularly attractive drug targets as both elements exist in reading frames that code other proteins (Tat and Env for Rev, Env for RRE), theoretically restricting potential escape mutations. However, to date there are no clinically approved therapies that target Rev-RRE.

Relationship to Other Viruses

All complex retroviruses face the problem of exporting unspliced and partially spliced mRNAs. Some use systems similar to Rev/RRE; these include HIV-2 and SIV (Simian Immunodeficiency Virus) which use their own Rev-RRE systems, some betaretroviruses, which use a Rem/RmRE system, and all deltaretroviruses which use a Rex/RxRRE systems. [21] [22]

Many simple retroviruses, most notably Mason–Pfizer monkey virus (MPMV), do not encode a Rev-like protein, but instead have evolved a cis-acting RNA element, the constitutive transport element (CTE), that directly binds to components of the host mRNA export machinery. The MPMV CTE is ~220 nucleotides and consists of two identical binding sites for the cellular export protein Tap. Tap directly binds the viral RNA and exports it to the cytoplasm. [23] [24]

See also

Related Research Articles

Nuclear pore

A nuclear pore is a part of a large complex of proteins, known as a nuclear pore complex that spans the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are approximately 1,000 nuclear pore complexes (NPCs) in the nuclear envelope of a vertebrate cell, but it varies depending on cell type and the stage in the life cycle. The human nuclear pore complex (hNPC) is a 110 megadalton (MDa) structure. The proteins that make up the nuclear pore complex are known as nucleoporins; each NPC contains at least 456 individual protein molecules and is composed of 34 distinct nucleoporin proteins. About half of the nucleoporins typically contain solenoid protein domains—either an alpha solenoid or a beta-propeller fold, or in some cases both as separate structural domains. The other half show structural characteristics typical of "natively unfolded" or intrinsically disordered proteins, i.e. they are highly flexible proteins that lack ordered tertiary structure. These disordered proteins are the FG nucleoporins, so called because their amino-acid sequence contains many phenylalanine—glycine repeats.

SR protein

SR proteins are a conserved family of proteins involved in RNA splicing. SR proteins are named because they contain a protein domain with long repeats of serine and arginine amino acid residues, whose standard abbreviations are "S" and "R" respectively. SR proteins are ~200-600 amino acids in length and composed of two domains, the RNA recognition motif (RRM) region and the RS domain. SR proteins are more commonly found in the nucleus than the cytoplasm, but several SR proteins are known to shuttle between the nucleus and the cytoplasm.

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The murine leukemia viruses are retroviruses named for their ability to cause cancer in murine (mouse) hosts. Some MLVs may infect other vertebrates. MLVs include both exogenous and endogenous viruses. Replicating MLVs have a positive sense, single-stranded RNA (ssRNA) genome that replicates through a DNA intermediate via the process of reverse transcription.

Env is a viral gene that encodes the protein forming the viral envelope. The expression of the env gene enables retroviruses to target and attach to specific cell types, and to infiltrate the target cell membrane.

Retroviral psi packaging element

The retroviral psi packaging element, also known as the Ψ RNA packaging signal, is a cis-acting RNA element identified in the genomes of the retroviruses Human immunodeficiency virus (HIV) and Simian immunodeficiency virus (SIV). It is involved in regulating the essential process of packaging the retroviral RNA genome into the viral capsid during replication. The final virion contains a dimer of two identical unspliced copies of the viral genome.

XPO1

Exportin 1 (XPO1), also known as chromosomal region maintenance 1 (CRM1), is a eukaryotic protein that mediates the nuclear export of various proteins and RNAs.

HNRNPA1

Heterogeneous nuclear ribonucleoprotein A1 is a protein that in humans is encoded by the HNRNPA1 gene. Mutations in hnRNP A1 are causative of amyotrophic lateral sclerosis and the syndrome multisystem proteinopathy.

NUP98

Nuclear pore complex protein Nup98-Nup96 is a protein that in humans is encoded by the NUP98 gene.

IPO5

Importin-5 is a protein that in humans is encoded by the IPO5 gene. The protein encoded by this gene is a member of the importin beta family. Structurally, the protein adopts the shape of a right hand solenoid and is composed of 24 HEAT repeats.

Transportin 1

Transportin-1 is a protein that in humans is encoded by the TNPO1 gene.

Nucleoporin 214

Nucleoporin 214 (Nup2014) is a protein that in humans is encoded by the NUP214 gene.

HRB (gene)

Arf-GAP domain and FG repeats-containing protein 1 is a protein that in humans is encoded by the AGFG1 gene.

DDX3X

ATP-dependent RNA helicase DDX3X is an enzyme that in humans is encoded by the DDX3X gene.

PTBP1

Polypyrimidine tract-binding protein 1 is a protein that in humans is encoded by the PTBP1 gene.

A nuclear export signal (NES) is a short target peptide containing 4 hydrophobic residues in a protein that targets it for export from the cell nucleus to the cytoplasm through the nuclear pore complex using nuclear transport. It has the opposite effect of a nuclear localization signal, which targets a protein located in the cytoplasm for import to the nucleus. The NES is recognized and bound by exportins.

HIV integration

AIDS is caused by the human immunodeficiency virus (HIV). Individuals with HIV have what is referred to as a "HIV infection". When infected semen, vaginal secretions, or blood come in contact with the mucous membranes or broken skin of an uninfected person, HIV may be transferred to the uninfected person, causing another infection. Additionally, HIV can also be passed from infected pregnant women to their uninfected baby during pregnancy and/or delivery, or via breastfeeding. As a result of HIV infection, a portion of these individuals will progress and go on to develop clinically significant AIDS.

Tat (HIV)

In molecular biology, Tat is a protein that is encoded for by the tat gene in HIV-1. Tat is a regulatory protein that drastically enhances the efficiency of viral transcription. Tat stands for "Trans-Activator of Transcription". The protein consists of between 86 and 101 amino acids depending on the subtype. Tat vastly increases the level of transcription of the HIV dsDNA. Before Tat is present, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat then binds to cellular factors and mediates their phosphorylation, resulting in increased transcription of all HIV genes, providing a positive feedback cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response.

Rev is a transactivating protein that is essential to the regulation of HIV-1 protein expression. A nuclear localization signal is encoded in the rev gene, which allows the Rev protein to be localized to the nucleus, where it is involved in the export of unspliced and incompletely spliced mRNAs. In the absence of Rev, mRNAs of the HIV-1 late (structural) genes are retained in the nucleus, preventing their translation.

Exon junction complex Protein complex assembled on mRNA

An exon junction complex (EJC) is a protein complex which forms on a pre-messenger RNA strand at the junction of two exons which have been joined together during RNA splicing. The EJC has major influences on translation, surveillance and localization of the spliced mRNA. It is first deposited onto mRNA during splicing and is then transported into the cytoplasm. There it plays a major role in post-transcriptional regulation of mRNA. It is believed that exon junction complexes provide a position-specific memory of the splicing event. The EJC consists of a stable heterotetramer core, which serves as a binding platform for other factors necessary for the mRNA pathway. The core of the EJC contains the protein eukaryotic initiation factor 4A-III bound to an adenosine triphosphate (ATP) analog, as well as the additional proteins Magoh and Y14.The binding of these proteins to nuclear speckled domains has been measured recently and it may be regulated by PI3K/AKT/mTOR signaling pathways. In order for the binding of the complex to the mRNA to occur, the eIF4AIII factor is inhibited, stopping the hydrolysis of ATP. This recognizes EJC as an ATP dependent complex. EJC also interacts with a large number of additional proteins; most notably SR proteins. These interactions are suggested to be important for mRNA compaction. The role of EJC in mRNA export is controversial.

References

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