Rev (HIV)

Last updated
REV protein bound to RRE mRNA
HIV-1 REV-RRE ribonucleoprotein complex.png
Shown above is the RNP complex formed by HIV-1 REV binding to the RRE upon mRNA of the env gene. Highlighted in slate is the ARM of the RNA binding domain, while colored in green is the mRNA with secondary stem-loop-like structure (PDB 4PMI).
Identifiers
SymbolREV
Pfam PF00424
InterPro IPR000625
SCOP2 484d / SCOPe / SUPFAM

Rev is a transactivating protein that is essential to the regulation of HIV-1 (and other lentiviral) 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.

Contents

History

A novel protein was found to be involved in the translation of gag and env mRNA. The unknown protein functioned by removing repression of regulatory sequences and was named Art (anti-repression transactivator). [1] Later studies suggested that the protein was involved in regulation of the RNA splicing mechanism. Therefore, the name of the protein was modified from Art to Trs (transregulator of splicing). [2] The most recent studies have shown that the protein has multiple functions in the regulation of HIV-1 proteins, and its name has been changed to Rev (regulator of expression of virion proteins), which more generally describes its function. [3]

Structure

Rev is a 13-kDa protein [4] that is composed of 116 amino acids. [5] Rev's sequence contains two specific domains which contribute to its nuclear import and export. The protein typically performs its function as a tetramer.[ citation needed ]

Arginine-rich motif

The N-terminal region of Rev contains an arginine-rich sequence. The arginine-rich motif (ARM) is located between amino acids 38–49 of the rev gene [6] and forms an alpha-helical secondary structure. [7] The ARM is a highly specific sequence which allows for the multimerization of Rev proteins, prior to RNA binding. A single base substitution alters Rev's ability to form a tetramer. [8] The arginine-rich domain of Rev interacts with the rev-binding element (RBE), which is part of the HIV Rev response element (RRE) located in an intron downstream of the env gene. [9] The alpha-helical secondary structure specifically can be considered a helix-loop-helix motif, which allows the REV protein to stably bind to the RRE RNA to form the ribonucleoprotein complex. [10] The domain also contains a nuclear localization signal. [11]

Rev-activation domain (Nuclear export signal)

Rev's nuclear export signal is located in residues 71–82 [12] of the C-terminal region [13] and is leucine-rich. [14] Binding of Rev to viral RNAs containing the RRE allows for mRNA export out of the nucleus and into the cytoplasm by a mechanism different than that of cellular mRNAs.[ citation needed ]

Function

HIV-1 regulatory proteins (including Rev) are translated from completely processed mRNA transcripts, while structural proteins are translated from incompletely spliced transcripts. Completely spliced transcripts are exported from the nucleus to the cytoplasm by the same mechanism as cellular mRNA. However, Rev is needed to export incompletely spliced mRNAs in order to produce the viral structural proteins.[ citation needed ]

Rev localization to the nucleus

The arginine-rich domain of the Rev protein, containing a nuclear localization signal (NLS), allows Rev to enter the nucleus. Entry requires binding between a Rev multimer, Ran-GDP, and importin-β (a nuclear transport factor). [15] The Rev NLS is a highly similar sequence to that of the importin-β-binding site present within importin-α, [16] which allows for the interaction between Rev and importin-β. The NLS overlaps with the sequence required for RNA-binding. [17] This prevents the NLS from counteracting the export of RRE-containing mRNA transcripts.[ citation needed ]

The secondary structure of the IIB binding site shows non-canonical base pairs G47 (magenta)-A73 (orange) and G48-G71 (magenta). Bulging, non-paired uridine nucleotide points outward from the secondary helix (colored red). The mRNA forms a stem-loop like structure with intricate folding (PDB 4PMI). RRE mRNA IIB binding site.png
The secondary structure of the IIB binding site shows non-canonical base pairs G47 (magenta)-A73 (orange) and G48-G71 (magenta). Bulging, non-paired uridine nucleotide points outward from the secondary helix (colored red). The mRNA forms a stem-loop like structure with intricate folding (PDB 4PMI).

Binding of Rev to the RRE

The rev response element (RRE) is a 240 base-pair sequence located in the second intron of the HIV-1 genome, immediately downstream of the env gene. [18] The RRE remains functional if translocated, but needs to remain in the same orientation (cannot be inverted). The RRE is retained by incompletely processed mRNA transcripts. The secondary structure of the RRE creates eight stem-loops. Rev initially binds to the purine-rich stem-loop IIB, [19] then binds to a secondary site in stem-loop I. [20]

Within this purine-rich stem-loop, IIB, are non-canonical base pairs that form as a result of the mRNA stem loop-secondary structure. These base pairs include guanine-adenine (nucleotides 47 and 73, respectively) and guanine-guanine (nucleotides 48–71, respectively). The two base pairs are separated by a non-stacked and bulging uridine that points outwards, away from the ARM-RNA interactions.

Shown are residues Arg35 and Arg39 (colored by element with IUPAC standards) that make specific contacts with residues uracil 66 (red), guanine 67, and guanine 70 (magenta) during RNA binding (PDB 4PMI). Specific contacts between ARM residues R39 and R35 and RRE mRNA nucleotides.png
Shown are residues Arg35 and Arg39 (colored by element with IUPAC standards) that make specific contacts with residues uracil 66 (red), guanine 67, and guanine 70 (magenta) during RNA binding (PDB 4PMI).

The ARM contains residues R35 and R39 that make base-specific contacts with residues on the RRE mRNA, specifically to bases uracil 66, guanine 67, and guanine 70, respectively. On the opposite side of these bases, residues N40 and R44 make base-specific contacts with nucleotides uracil 45, guanine 46, guanine 47, and adenine 73. In addition to these stabilizing contacts, additional Arg residues within the ARM, as well as T34, make nonspecific contacts with bases on the mRNA. [21]

Shown are residues N40 and R44 (colored by element with IUPAC standards) making specific contacts with residues uracil 45 (red), guanine 46 (magenta), guanine 47 (magenta), and adenine 73 (orange) (PDB 4PMI). Specific contacts between ARM residues R44 and N40 with RRE mRNA nucleotides.png
Shown are residues N40 and R44 (colored by element with IUPAC standards) making specific contacts with residues uracil 45 (red), guanine 46 (magenta), guanine 47 (magenta), and adenine 73 (orange) (PDB 4PMI).

The RRE sequence is cis-acting, and is necessary to achieve high levels of env mRNA in the cytoplasm. [22] The RRE also facilitates multimerization of the Rev proteins, which is required for Rev binding and function. [23] The Rev protein binds unspliced gag and pol transcripts and incompletely spliced env, vif, vpr and vpu transcripts at the RRE, facilitating export to the cytoplasm. [24]

Genomic export from the nucleus

Rev is continuously shuttled between the cytoplasm and nucleus. The shuttling of Rev is regulated by its nuclear localization signal and its nuclear export signal. Once Rev is inside the nucleus, Ran-GDP is phosphorylated into Ran-GTP, causing the importation complex to disassemble. Upon disassembly, Rev's NES forms a new complex with CRM1 (exportin-1) and Ran-GTP at the RRE sequence within incompletely spliced transcripts. Following assembly of the complex, the intron-containing RNAs are exported from the nucleus into the cytoplasm. [25] Once the pre-mRNAs are in the cytoplasm, Rev dissociates, revealing the NLS. [26] Exposure of the NLS allows for Rev interaction with importin-β in order to shuttle Rev back to the nucleus.[ citation needed ]

Rev-directed export of viral RNAs is similar to the mechanism by which snRNAs and the 5s rRNAs are exported, as opposed to the mechanism for export of cellular mRNAs. Rev is able to facilitate export of pre-mRNA transcripts that would otherwise typically remain in the nucleus, suggesting that the Rev NES is dominant over nuclear retention. [27]

Regulation of HIV gene expression

Rev acts post-transcriptionally to positively regulate the expression of structural genes and to negatively regulate the expression of regulatory genes. Rev positively regulates the expression of gag, pol, and env. Rev-mediated export from the nucleus increases cytoplasmic levels of the structural mRNAs (gag, pol, and env). [28] Gag, pol and env expression is lower in the absence of Rev and higher in the presence of Rev. [29] Rev negatively regulates the expression of the regulatory genes (rev and tat) by creating a negative feedback loop, which regulates Rev production. There is a decrease in Rev production when Rev protein levels are higher than is necessary for the given amount of HIV-1 genome encoded. Rev also decreases the quantity of completely spliced viral messages expressed by exporting pre-mRNA before it can be spliced. This results in decreased expression of the regulatory proteins, Rev and Tat. Since Rev is continuously shuttled between the nucleus and cytoplasm, small amounts of the protein are able to impact many mRNA transcripts. Maintenance of the proper balance between early and late viral gene quantities leads to an overall increase in virion production. [30]

Transition from early to late phase HIV-1 genes

HIV-1 genes are expressed from either completely spliced RNA or from intron-containing RNA. The export of fully spliced mRNAs (early, regulatory genes) occurs in the same manner as the normal export of cellular mRNAs. On the other hand, unspliced and incompletely spliced mRNAs which code for the late, structural proteins are Rev-dependent. The Rev protein is expressed as an early gene from completely spliced transcripts, so the expression of late phase structural proteins cannot occur until an initial amount of Rev is produced. [31]

Rev as a target for antiviral therapies

Since Rev is absolutely necessary for HIV-1 replication and it is expressed early on in infection, it has been suggested that Rev is a good target for antiviral therapies.[ citation needed ]

Leptomycin B (LMB) binds to CRM1 which prevents the formation of the complex required for export(CRM1/NES/RanGTP/RRE) and ultimately reduces the production of incompletely spliced RNAs. [32] [33] Therefore, structural proteins, which are necessary for virion assembly, are not produced.

It has been shown that various organic compounds have the ability to target the Rev/RRE interaction. Neomycin B, diphenylfuran cation, and proflavine are small molecules that can prevent Rev from binding to the RRE sequence. [34] [35] [36] If Rev is incapable of binding to the RRE on the pre-mRNA, the RNA will not be exported to the cytoplasm, also resulting in lack of necessary structural proteins.[ citation needed ]

Other therapies target the Rev protein itself, since it is an essential component of HIV-1 infection. M10 is a mutated form of Rev and has a single amino acid substitution (Aspartic acid to Leucine). If delivered to cells, Rev M10 will compete with the wild-type Rev protein for the RRE binding site, and therefore decrease Rev's normal cellular functions. [37]

Dihydrovaltrate was also identified as a Rev-export inhibitory congener.[ citation needed ]

Related Research Articles

Cell nucleus Eukaryotic membrane-bounded organelle containing DNA

In cell biology, the nucleus is a membrane-bound organelle found in eukaryotic cells. Eukaryotes usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have no nuclei, and a few others including osteoclasts have many. The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm; and the nuclear matrix, a network within the nucleus that adds mechanical support, much like the cytoskeleton supports the cell as a whole.

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 this number 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.

Retrovirus Family of viruses

A retrovirus is a type of virus that inserts a copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus.

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.

The genome and proteins of HIV have been the subject of extensive research since the discovery of the virus in 1983. "In the search for the causative agent, it was initially believed that the virus was a form of the Human T-cell leukemia virus (HTLV), which was known at the time to affect the human immune system and cause certain leukemias. However, researchers at the Pasteur Institute in Paris isolated a previously unknown and genetically distinct retrovirus in patients with AIDS which was later named HIV." Each virion comprises a viral envelope and associated matrix enclosing a capsid, which itself encloses two copies of the single-stranded RNA genome and several enzymes. The discovery of the virus itself occurred two years following the report of the first major cases of AIDS-associated illnesses.

Importin is a type of karyopherin that transports protein molecules from the cell's cytoplasm to the nucleus. It does so by binding to specific recognition sequences, called nuclear localization sequences (NLS).

Nuclear transport

Nuclear transport refers to the mechanisms by which molecules move across the nuclear membrane of a cell. The entry and exit of large molecules from the cell nucleus is tightly controlled by the nuclear pore complexes (NPCs). Although small molecules can enter the nucleus without regulation, macromolecules such as RNA and proteins require association with transport factors known as nuclear transport receptors, like karyopherins called importins to enter the nucleus and exportins to exit.

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.

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.

HNRNPA1 Protein-coding gene in the species Homo sapiens

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.

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.

KPNA5

Importin subunit alpha-6 is a protein that in humans is encoded by the KPNA5 gene.

RBM8A Protein-coding gene in the species Homo sapiens

RNA-binding protein 8A is a protein that in humans is encoded by the RBM8A gene.

Transportin 1

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

Nucleoporin 214 Protein-coding gene in the species Homo sapiens

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.

PTBP1 Protein-coding gene in the species Homo sapiens

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

Serine/arginine-rich splicing factor 1

Serine/arginine-rich splicing factor 1 (SRSF1) also known as alternative splicing factor 1 (ASF1), pre-mRNA-splicing factor SF2 (SF2) or ASF1/SF2 is a protein that in humans is encoded by the SRSF1 gene. ASF/SF2 is an essential sequence specific splicing factor involved in pre-mRNA splicing. SRSF1 is the gene that codes for ASF/SF2 and is found on chromosome 17. The resulting splicing factor is a protein of approximately 33 kDa. ASF/SF2 is necessary for all splicing reactions to occur, and influences splice site selection in a concentration-dependent manner, resulting in alternative splicing. In addition to being involved in the splicing process, ASF/SF2 also mediates post-splicing activities, such as mRNA nuclear export and translation.

Bovine immunodeficiency virus (BIV) is a retrovirus belonging to the genus Lentivirus. It is similar to the human immunodeficiency virus (HIV) and infects cattle. The cells primarily infected are lymphocytes and monocytes/macrophages.

Importin alpha, or karyopherin alpha refers to a class of adaptor proteins that are involved in the import of proteins into the cell nucleus. They are a sub-family of karyopherin proteins.

References

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  18. ↑ Hadzopoulou-Cladaras M, Felber BK, Cladaras C, Athanassopoulos A, Tse A, Pavlakis GN (March 1989). "The rev (trs/art) protein of human immunodeficiency virus type 1 affects viral mRNA and protein expression via a cis-acting sequence in the env region". Journal of Virology. 63 (3): 1265–74. doi:10.1128/JVI.63.3.1265-1274.1989. PMC   247823 . PMID   2783738.
  19. ↑ Nakatani K, Horie S, Goto Y, Kobori A, Hagihara S (August 2006). "Evaluation of mismatch-binding ligands as inhibitors for Rev-RRE interaction". Bioorganic & Medicinal Chemistry. 14 (15): 5384–8. doi:10.1016/j.bmc.2006.03.038. PMID   16603366.
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  23. ↑ Zapp ML, Hope TJ, Parslow TG, Green MR (September 1991). "Oligomerization and RNA binding domains of the type 1 human immunodeficiency virus Rev protein: a dual function for an arginine-rich binding motif". Proceedings of the National Academy of Sciences of the United States of America. 88 (17): 7734–8. Bibcode:1991PNAS...88.7734Z. doi: 10.1073/pnas.88.17.7734 . PMC   52377 . PMID   1715576.
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  27. ↑ Fischer U, Huber J, Boelens WC, Mattaj IW, Lührmann R (August 1995). "The HIV-1 Rev activation domain is a nuclear export signal that accesses an export pathway used by specific cellular RNAs". Cell. 82 (3): 475–83. doi: 10.1016/0092-8674(95)90436-0 . PMID   7543368. S2CID   15414237.
  28. ↑ Feinberg MB, Jarrett RF, Aldovini A, Gallo RC, Wong-Staal F (September 1986). "HTLV-III expression and production involve complex regulation at the levels of splicing and translation of viral RNA". Cell. 46 (6): 807–17. doi:10.1016/0092-8674(86)90062-0. PMID   3638988. S2CID   37813869.
  29. ↑ Hadzopoulou-Cladaras M, Felber BK, Cladaras C, Athanassopoulos A, Tse A, Pavlakis GN (March 1989). "The rev (trs/art) protein of human immunodeficiency virus type 1 affects viral mRNA and protein expression via a cis-acting sequence in the env region". Journal of Virology. 63 (3): 1265–74. doi:10.1128/JVI.63.3.1265-1274.1989. PMC   247823 . PMID   2783738.
  30. ↑ Hope TJ (May 1999). "The ins and outs of HIV Rev". Archives of Biochemistry and Biophysics. 365 (2): 186–91. doi:10.1006/abbi.1999.1207. PMID   10328811.
  31. ↑ Felber BK, Drysdale CM, Pavlakis GN (August 1990). "Feedback regulation of human immunodeficiency virus type 1 expression by the Rev protein". Journal of Virology. 64 (8): 3734–41. doi:10.1128/JVI.64.8.3734-3741.1990. PMC   249668 . PMID   2196381.
  32. ↑ Fornerod M, Ohno M, Yoshida M, Mattaj IW (September 1997). "CRM1 is an export receptor for leucine-rich nuclear export signals". Cell. 90 (6): 1051–60. doi: 10.1016/s0092-8674(00)80371-2 . PMID   9323133. S2CID   15119502.
  33. ↑ Xiao G, Kumar A, Li K, Rigl CT, Bajic M, Davis TM, et al. (May 2001). "Inhibition of the HIV-1 rev-RRE complex formation by unfused aromatic cations". Bioorganic & Medicinal Chemistry. 9 (5): 1097–113. doi:10.1016/s0968-0896(00)00344-8. PMID   11377168.
  34. ↑ Baba M (2004). "Inhibitors of HIV-1 gene expression and transcription". Current Topics in Medicinal Chemistry. 4 (9): 871–82. doi:10.2174/1568026043388466. PMID   15134546.
  35. ↑ DeJong ES, Chang CE, Gilson MK, Marino JP (July 2003). "Proflavine acts as a Rev inhibitor by targeting the high-affinity Rev binding site of the Rev responsive element of HIV-1". Biochemistry. 42 (26): 8035–46. doi:10.1021/bi034252z. PMID   12834355.
  36. ↑ Xiao G, Kumar A, Li K, Rigl CT, Bajic M, Davis TM, et al. (May 2001). "Inhibition of the HIV-1 rev-RRE complex formation by unfused aromatic cations". Bioorganic & Medicinal Chemistry. 9 (5): 1097–113. doi:10.1016/s0968-0896(00)00344-8. PMID   11377168.
  37. ↑ Plavec I, Agarwal M, Ho KE, Pineda M, Auten J, Baker J, et al. (February 1997). "High transdominant RevM10 protein levels are required to inhibit HIV-1 replication in cell lines and primary T cells: implication for gene therapy of AIDS". Gene Therapy. 4 (2): 128–39. doi: 10.1038/sj.gt.3300369 . PMID   9081703.
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