Adenovirus early region 1A

Last updated

Adenovirus early region 1A (E1A) is a gene expressed during adenovirus replication to produce a variety of E1A proteins. [1] It is expressed during the early phase of the viral life span.

Contents

E1A encodes two major proteins in Ad5, translated after alternative splicing of the viral DNA transcript, that are able to cause a variety of different effects in mammalian cells. [2] The proteins encoded by E1A tend to localize in the nucleus and affect genetic regulation by the host cell. [1] After viral infection, they stimulate expression of other viral genes and can either enhance or repress expression of cellular genes depending on cellular context and coordination with other viral genes. [3]

The addition of E1A DNA into cells may cause adverse biological effects, [4] such as increasing p53 expression, [5] stimulating DNA synthesis and cell cycle progression in quiescent cells, [2] and inhibiting differentiation. [6] It has been considered an oncogene. [7] It can also behave as a tumour suppressor gene. [8] [3]

Transcription

Figure 1: Structure of the E1A mRNA transcripts, coding regions are represented as boxes Transcript.png
Figure 1: Structure of the E1A mRNA transcripts, coding regions are represented as boxes

The adenovirus genetic information is encoded by a double stranded linear DNA molecule. During viral replication, adenovirus early region 1A (E1A) is a gene that is expressed. The majority of work on adenovirus transcription has focused on human adenovirus, specifically Ad2 and Ad5. The complete nucleotide sequence of E1A has been established, and the overall organization of this region appears to be very similar to that of the various serotypes. [9]

Almost an hour after viral infection, the virus undergoes transcription to form a primary gene E1A which undergoes alternative splicing, a regulated process where multiple protein isoforms are encoded by a primary gene via exons, parts of exons or introns being differentially joined or skipped. The E1A is spliced differentially into five transcripts with sedimentation coefficients of 13S, 12S, 11S, 10S and 9S, [10] all of which have been known to code for different proteins with varying numbers of amino acid residues of 289R, 243R, 217R, 171R, 55R, respectively, each performing different functions. [1] The 289R and 243R proteins are the major products encoded by the E1A of Ad5. These two proteins share almost the same internal sequences as shown in the figure except for the 46 internal amino acids unique to the 289 protein which is as a result of the differential splicing. These proteins are functionally important for growth of adenoviruses. [11]

Translation

The adenovirus early region 1A gene is translated to produce E1A proteins by using the host cell’s molecular machinery. Early proteins are produced after the virus enters the host cell, but before replication. This is in contrast to late proteins which are produced from late phase genes. Early proteins typically encode non-structural proteins that are necessary for replication, whereas late structural proteins typically function to initiate gene expression. The E1A gene refers to the gene that encodes E1A proteins specifically involved in adenovirus replication.[ citation needed ]

In the adenovirus, the final translation products, or E1A proteins, are proline-rich and have been found to localize in the nucleus. These protein products play a role in regulating the gene itself and in growth activities of the virus. [1]

The mRNA transcripts, 13S, 12S, 11S, 10S and 9S, each code for the following respective protein residues: 289 residue (R), 243R, 217R, 171R and 55R. These products are involved in the regulation of viral genes as well as the genes in the infected cell. [1]

Adenovirus protein regulation of viral genes has been studied in adenovirus type-5, or Ad5. Ad5 refers to a specific group of human adenoviruses. In Ad5-infected cells, E1A translation was hypothesized to involve the Ad5 L4 100-kDa protein. It was concluded that this protein is involved in translation initiation for subsequent late phase proteins. [12]

With regards to cellular translation of the host cell, it has been concluded that adenovirus selectively inhibits cellular translation via displacement of MAP kinase-interacting serine/threonine-protein kinase 1 (Mnk1), an eukaryotic translation initiation factor. Adenovirus likely displaces Mnk1 from eIF4G and inhibits eIF4E phosphorylation, both of which are important components of the eIF4a translation initiation complex in cells. While adenovirus likely blocks cellular translation in this way, it does not affect the translation of its own viral mRNAs. [13]

Structures of protein products

The adenovirus early region 1A (E1A) 289R protein is composed of 289 amino acids, with four conserved regions: CR1 (42-80), CR2 (115-137), CR3 (145-191), [14] CR4 (240-289). In 243R, the CR3 is absent. These conserved domains are responsible for the protein-protein interaction and the regulation of cell cycling and cellular responses. Overall, the intrinsic structure of E1A is highly disordered, meaning that it lacks a single, three-dimensional structure. [15]

Figure 2: The construct of E1A proteins. E1aproteinconstruct.png
Figure 2: The construct of E1A proteins.

However, the structure of E1A can be fixed upon the ligand binding. The structure of cyclic-AMP response element binding protein (CBP) and E1A complex was determined by NMR. It reveals that CR1 and CR2 are responsible for the CBP interaction to regulate the cell transformation. The CR1 domain is formed by the random coils without advanced structure in free state. However, when bound to the zinc finger-2 domain of CBP, it folds into a helical structure. [16]

The CR3 is a distinct domain in 289R since it is the only domain with advanced structure. The fixed structure allows this domain to recognize TATA-binding protein (TBP) and activate transcription of certain genes. The residue Val147 within CR3 is a critical residue for the TBP interaction.  It is proposed that the mutation of Val will interrupt the hydrophobic environments at the binding site leading to a disabling of the TBP interaction, indicating the structure of CR3 is a key domain for TBP interaction. [2]

Role in viral life cycle

It has been found that the E1A C-terminus (encoded by the second exon) is heavily influential in adenovirus replicative cycle, impacting processes of replication, localization, growth, gene expression, protein expression, and notably induction of the S-Phase. This particularly encoded C-Terminus region is characteristic of all E1A isoforms with the exception of 55 residues protein. [17]

By examining binding factors, scientist have better understood the impacts of the C-terminus on viral life cycle: E1A direct binding of RubBL1 repressing gene activation induced by interferons, and Ku70 being an inhibitor of DNA response to damage. [18] [19] Additionally, mutations observed on the E1A C-terminus were found to have impacts on S-phase induction and deletions to the terminus showed varying impacts on growth of virus. However, while we are aware of some of the ways C-terminus works to impact viral life cycle, a comprehensive understanding is not yet fully understood. [17]

Effects on host cell

The natural host cell-type targeted by adenoviruses are G0-arrested quiescent cells, and it has been proposed that for this reason adenovirus genes stimulate proliferation of these cells in order to maximize viral replication. Proteins encoded by E1A can have varying effects on host cellular operations as well as its host organism, depending on many factors, most notably on if the gene is acting alone or in cooperativity with other adenovirus genes, such as E1B. On its own, E1A is able to affect gene function in order to stimulate quiescent cells to divide, repress differentiation, and induce apoptosis. When in coordination with E1B or other oncogenic genes such as activated ras, E1A is able to transform rodent cells oncogenically. [20]

It has been found that within 24 hours of expression on its own, E1A binds transiently to gene clusters/promoters involved in pathogen and immune response as well as those regulating cell growth, development, differentiation, division, and DNA synthesis in human fibroblast cells, with the effect of repressing their activation. Additionally, E1A is able to reprogram cells on an epigenetic basis. Interaction of E1A with p300/CBP histone acetyltransferases causes a reduction in total cellular acetylation of H3K18 by roughly a factor of 3, which may be similar in mechanism to nonviral forms of oncogenesis. The combined effect of E1A promoter binding and epigenetic changes act to promote host cell entry into S phase and repress differentiation. [21]

E1A protein products interfere with host immunity through a number of distinct interactions with innate cellular signalling pathways. By blocking transcription complex formation by binding transcription factors, preventing ubiquitination of certain histones, and blocking peptide degradation by the immunoproteasome, E1A is able to reduce antigen presentation on adenovirus-infected cells and disrupt the cell’s innate immune response. [22]

Related Research Articles

<i>Adenoviridae</i> Family of viruses

Adenoviruses are medium-sized, nonenveloped viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from their initial isolation from human adenoids in 1953.

In molecular biology, the TATA box is a sequence of DNA found in the core promoter region of genes in archaea and eukaryotes. The bacterial homolog of the TATA box is called the Pribnow box which has a shorter consensus sequence.

Viral pathogenesis is the study of the process and mechanisms by which viruses cause diseases in their target hosts, often at the cellular or molecular level. It is a specialized field of study in virology.

<span class="mw-page-title-main">TATA-binding protein</span> Protein-coding gene in the species Homo sapiens

The TATA-binding protein (TBP) is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 30 base pairs upstream of the transcription start site in some eukaryotic gene promoters.

<span class="mw-page-title-main">SV40 large T antigen</span> Proto-oncogene derived from polyomavirus SV40

SV40 large T antigen is a hexamer protein that is a dominant-acting oncoprotein derived from the polyomavirus SV40. TAg is capable of inducing malignant transformation of a variety of cell types. The transforming activity of TAg is due in large part to its perturbation of the retinoblastoma (pRb) and p53 tumor suppressor proteins. In addition, TAg binds to several other cellular factors, including the transcriptional co-activators p300 and CBP, which may contribute to its transformation function. Similar proteins from related viruses are known as large tumor antigen in general.

Adenovirus E1B protein usually refers to one of two proteins transcribed from the E1B gene of the adenovirus: a 55kDa protein and a 19kDa protein. These two proteins are needed to block apoptosis in adenovirus-infected cells. E1B proteins work to prevent apoptosis that is induced by the small adenovirus E1A protein, which stabilizes p53, a tumor suppressor.

<span class="mw-page-title-main">Retinoblastoma-like protein 2</span> Protein-coding gene in the species Homo sapiens

Retinoblastoma-like protein 2 is a protein that in humans is encoded by the RBL2 gene.

<span class="mw-page-title-main">HNRNPA1</span> 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.

<span class="mw-page-title-main">Y box binding protein 1</span> Protein-coding gene in the species Homo sapiens

Y box binding protein 1 also known as Y-box transcription factor or nuclease-sensitive element-binding protein 1 is a protein that in humans is encoded by the YBX1 gene.

<span class="mw-page-title-main">CTBP1</span> Protein-coding gene in the species Homo sapiens

C-terminal-binding protein 1 also known as CtBP1 is a protein that in humans is encoded by the CTBP1 gene. CtBP1 is one of two CtBP proteins, the other protein being CtBP2.

<span class="mw-page-title-main">Retinoblastoma-like protein 1</span> Mammalian protein found in Homo sapiens

Retinoblastoma-like 1 (p107), also known as RBL1, is a protein that in humans is encoded by the RBL1 gene.

<span class="mw-page-title-main">RBBP8</span> Protein-coding gene in the species Homo sapiens

Retinoblastoma-binding protein 8 is a protein that in humans is encoded by the RBBP8 gene.

<span class="mw-page-title-main">CREG1</span> Protein-coding gene in the species Homo sapiens

Protein CREG1 is a protein that in humans is encoded by the CREG1 gene.

<span class="mw-page-title-main">Vpu protein</span>

Vpu is an accessory protein that in HIV is encoded by the vpu gene. Vpu stands for "Viral Protein U". The Vpu protein acts in the degradation of CD4 in the endoplasmic reticulum and in the enhancement of virion release from the plasma membrane of infected cells. Vpu induces the degradation of the CD4 viral receptor and therefore participates in the general downregulation of CD4 expression during the course of HIV infection. Vpu-mediated CD4 degradation is thought to prevent CD4-Env binding in the endoplasmic reticulum to facilitate proper Env assembly into virions. It is found in the membranes of infected cells, but not the virus particles themselves.

<span class="mw-page-title-main">Rev (HIV)</span> HIV-1 regulating protein

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.

Adenovirus varieties have been explored extensively as a viral vector for gene therapy and also as an oncolytic virus.

<span class="mw-page-title-main">Large tumor antigen</span>

The large tumor antigen is a protein encoded in the genomes of polyomaviruses, which are small double-stranded DNA viruses. LTag is expressed early in the infectious cycle and is essential for viral proliferation. Containing four well-conserved protein domains as well as several intrinsically disordered regions, LTag is a fairly large multifunctional protein; in most polyomaviruses, it ranges from around 600-800 amino acids in length. LTag has two primary functions, both related to replication of the viral genome: it unwinds the virus's DNA to prepare it for replication, and it interacts with proteins in the host cell to dysregulate the cell cycle so that the host's DNA replication machinery can be used to replicate the virus's genome. Some polyomavirus LTag proteins - most notably the well-studied SV40 large tumor antigen from the SV40 virus - are oncoproteins that can induce neoplastic transformation in the host cell.

<span class="mw-page-title-main">Small tumor antigen</span>

The small tumor antigen is a protein encoded in the genomes of polyomaviruses, which are small double-stranded DNA viruses. STag is expressed early in the infectious cycle and is usually not essential for viral proliferation, though in most polyomaviruses it does improve replication efficiency. The STag protein is expressed from a gene that overlaps the large tumor antigen (LTag) such that the two proteins share an N-terminal DnaJ-like domain but have distinct C-terminal regions. STag is known to interact with host cell proteins, most notably protein phosphatase 2A (PP2A), and may activate the expression of cellular proteins associated with the cell cycle transition to S phase. In some polyomaviruses - such as the well-studied SV40, which natively infects monkeys - STag is unable to induce neoplastic transformation in the host cell on its own, but its presence may increase the transforming efficiency of LTag. In other polyomaviruses, such as Merkel cell polyomavirus, which causes Merkel cell carcinoma in humans, STag appears to be important for replication and to be an oncoprotein in its own right.

The middle tumor antigen is a protein encoded in the genomes of some polyomaviruses, which are small double-stranded DNA viruses. MTag is expressed early in the infectious cycle along with two other related proteins, the small tumor antigen and large tumor antigen. MTag occurs only in a few known polyomaviruses, while STag and LTag are universal - it was first identified in mouse polyomavirus (MPyV), the first polyomavirus discovered, and also occurs in hamster polyomavirus. In MPyV, MTag is an efficient oncoprotein that can be sufficient to induce neoplastic transformation in some cells.

<span class="mw-page-title-main">Coronavirus envelope protein</span> Major structure in coronaviruses

The envelope (E) protein is the smallest and least well-characterized of the four major structural proteins found in coronavirus virions. It is an integral membrane protein less than 110 amino acid residues long; in SARS-CoV-2, the causative agent of Covid-19, the E protein is 75 residues long. Although it is not necessarily essential for viral replication, absence of the E protein may produce abnormally assembled viral capsids or reduced replication. E is a multifunctional protein and, in addition to its role as a structural protein in the viral capsid, it is thought to be involved in viral assembly, likely functions as a viroporin, and is involved in viral pathogenesis.

References

  1. 1 2 3 4 5 "Introduction To Ad5 E1A".
  2. 1 2 3 Molloy DP, Smith KJ, Milner AE, Gallimore PH, Grand RJ (February 1999). "The structure of the site on adenovirus early region 1A responsible for binding to TATA-binding protein determined by NMR spectroscopy". The Journal of Biological Chemistry. 274 (6): 3503–3512. doi: 10.1074/jbc.274.6.3503 . PMID   9920896.
  3. 1 2 Frisch SM, Mymryk JS (June 2002). "Adenovirus-5 E1A: paradox and paradigm". Nature Reviews. Molecular Cell Biology. 3 (6): 441–452. doi:10.1038/nrm827. PMID   12042766. S2CID   20282450.
  4. ↑ Boulanger PA, Blair GE (April 1991). "Expression and interactions of human adenovirus oncoproteins". The Biochemical Journal. 275 ( Pt 2) (Pt 2): 281–299. doi:10.1042/bj2750281. PMC   1150051 . PMID   1827253.
  5. ↑ Rao L, Debbas M, Sabbatini P, Hockenbery D, Korsmeyer S, White E (August 1992). "The adenovirus E1A proteins induce apoptosis, which is inhibited by the E1B 19-kDa and Bcl-2 proteins". Proceedings of the National Academy of Sciences of the United States of America. 89 (16): 7742–7746. Bibcode:1992PNAS...89.7742R. doi: 10.1073/pnas.89.16.7742 . PMC   49787 . PMID   1457005.
  6. ↑ Webster KA, Muscat GE, Kedes L (April 1988). "Adenovirus E1A products suppress myogenic differentiation and inhibit transcription from muscle-specific promoters". Nature. 332 (6164): 553–557. Bibcode:1988Natur.332..553W. doi:10.1038/332553a0. PMID   2965790. S2CID   4355283.
  7. ↑ Routes JM, Ryan S, Clase A, Miura T, Kuhl A, Potter TA, Cook JL (October 2000). "Adenovirus E1A oncogene expression in tumor cells enhances killing by TNF-related apoptosis-inducing ligand (TRAIL)". Journal of Immunology. 165 (8): 4522–4527. doi: 10.4049/jimmunol.165.8.4522 . PMID   11035092.
  8. ↑ Frisch SM (May 2004). "E1A as a tumor suppressor gene: commentary re S. Madhusudan et al. A multicenter Phase I gene therapy clinical trial involving intraperitoneal administration of E1A-lipid complex in patients with recurrent epithelial ovarian cancer overexpressing HER-2/neu oncogene". Clinical Cancer Research. 10 (9): 2905–2907. doi: 10.1158/1078-0432.CCR-04-0644 . PMID   15131023.
  9. ↑ Grand RJ (January 1987). "The structure and functions of the adenovirus early region 1 proteins". The Biochemical Journal. 241 (1): 25–38. doi:10.1042/bj2410025. PMC   1147520 . PMID   2952111.
  10. ↑ "The Adenovirus 5 E1A Page". publish.uwo.ca. Retrieved 2020-10-22.
  11. ↑ Spindler KR, Eng CY, Berk AJ (March 1985). "An adenovirus early region 1A protein is required for maximal viral DNA replication in growth-arrested human cells". Journal of Virology. 53 (3): 742–750. doi:10.1128/JVI.53.3.742-750.1985. PMC   254702 . PMID   3973965.
  12. ↑ Hayes BW, Telling GC, Myat MM, Williams JF, Flint SJ (June 1990). "The adenovirus L4 100-kilodalton protein is necessary for efficient translation of viral late mRNA species". Journal of Virology. 64 (6): 2732–2742. doi:10.1128/JVI.64.6.2732-2742.1990. PMC   249453 . PMID   2335816.
  13. ↑ Cuesta R, Xi Q, Schneider RJ (July 2000). "Adenovirus-specific translation by displacement of kinase Mnk1 from cap-initiation complex eIF4F". The EMBO Journal. 19 (13): 3465–3474. doi:10.1093/emboj/19.13.3465. PMC   313943 . PMID   10880459.
  14. ↑ Singh G, Ismail AM, Lee JY, Ramke M, Lee JS, Dyer DW, et al. (February 2019). "Divergent Evolution of E1A CR3 in Human Adenovirus Species D". Viruses. 11 (2): 143. doi: 10.3390/v11020143 . PMC   6409611 . PMID   30744049.
  15. ↑ Pelka P, Ablack JN, Fonseca GJ, Yousef AF, Mymryk JS (August 2008). "Intrinsic structural disorder in adenovirus E1A: a viral molecular hub linking multiple diverse processes". Journal of Virology. 82 (15): 7252–7263. doi: 10.1128/JVI.00104-08 . PMC   2493305 . PMID   18385237.
  16. ↑ Ferreon JC, Martinez-Yamout MA, Dyson HJ, Wright PE (August 2009). "Structural basis for subversion of cellular control mechanisms by the adenoviral E1A oncoprotein". Proceedings of the National Academy of Sciences of the United States of America. 106 (32): 13260–13265. Bibcode:2009PNAS..10613260F. doi: 10.1073/pnas.0906770106 . PMC   2726373 . PMID   19651603.
  17. 1 2 Crisostomo L, Soriano AM, Frost JR, Olanubi O, Mendez M, Pelka P (December 2017). "The Influence of E1A C-Terminus on Adenovirus Replicative Cycle". Viruses. 9 (12): 387. doi: 10.3390/v9120387 . PMC   5744161 . PMID   29257057.
  18. ↑ Olanubi O, Frost JR, Radko S, Pelka P (April 2017). Banks L (ed.). "Suppression of Type I Interferon Signaling by E1A via RuvBL1/Pontin". Journal of Virology. 91 (8): e02484–16, e02484–16. doi: 10.1128/JVI.02484-16 . PMC   5375691 . PMID   28122980.
  19. ↑ Frost JR, Olanubi O, Cheng SK, Soriano A, Crisostomo L, Lopez A, Pelka P (January 2017). "The interaction of adenovirus E1A with the mammalian protein Ku70/XRCC6". Virology. 500: 11–21. doi:10.1016/j.virol.2016.10.004. PMID   27769014.
  20. ↑ Bayley ST, Mymryk JS (September 1994). "Adenovirus e1a proteins and transformation (review)". International Journal of Oncology. 5 (3): 425–444. doi:10.3892/ijo.5.3.425. PMID   21559595.
  21. ↑ Ferrari R, Pellegrini M, Horwitz GA, Xie W, Berk AJ, Kurdistani SK (August 2008). "Epigenetic reprogramming by adenovirus e1a". Science. 321 (5892): 1086–1088. Bibcode:2008Sci...321.1086F. doi:10.1126/science.1155546. PMC   2693122 . PMID   18719284.
  22. ↑ Hendrickx R, Stichling N, Koelen J, Kuryk L, Lipiec A, Greber UF (April 2014). "Innate immunity to adenovirus". Human Gene Therapy. 25 (4): 265–284. doi:10.1089/hum.2014.001. PMC   3996939 . PMID   24512150.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.