Adenovirus E1B protein

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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. [1] [2]

Contents

Functions

E1B-19k

E1B-19k blocks a p53-independent apoptosis mechanism. Without E1B-19k, degradation of both cellular and viral DNA occurs, in addition to premature host cell death during the lytic cycle, thus limiting viral replication. [3] E1B-19k mimics MCL1, which is a cellular antiapoptotic protein. [4] In infected cells, the expression of E1A results in the degradation of MCL-1, which normally binds the propaptotic protein, BAK. [4] BAK activation induces apoptosis by cooligomerizing with another proapoptotic protein, BAX. Together, BAK and BAX form pores in the mitochondrial membrane, releasing apoptogenic proteins like cytochrome c. [3] [5] This and other proteins released from the mitochondria lead to activation of caspase-9 and caspase-3 and the resulting apoptotic program. [6] However, in adenovirus-infected cells, activated BAK and BAX are sequestered by E1B-19k, preventing the pathway. [3]

E1B-55k

E1B-55k blocks p53 from inhibiting cell cycling and stops it from inducing apoptosis. [7] Observations show that E1b-55k inhibits activation by p53 by binding a repression domain to it, converting it from an activator to a repressor of p53-activated genes. This stabilizes p53 and causes a large increase in p53 concentration. Additionally, p53 bound to E1B-55k has an affinity for its binding site that is ten times higher than free p53. [8] Presumably, this increased affinity and concentration of p53 turns the p53-E1B-55k complex into a powerful repressor. [9]

E1B-55k also forms a complex with E4orf6, a viral protein. [10] The E1B-55k/E4orf6 complex in infected cells assembles with other cellular proteins to form a ubiquitin ligase complex. [11] Essentially, the E1B-55k/E4orf6 complex takes over the cellular ubiquitin ligase complexes and gives them viral substrate-recognition subunits. [9] There are two known substrates for this ubiquitin ligases; p53 and the MRN complex. [11] [12] The MRN complex, if not bound by the E1B-55K/E4orf6 ubiquitin ligase, will treat the ends of the viral DNA like a double-stranded DNA break and the viral DNA becomes ligated into long concatemers of randomly assorted genomes. [13]

Structural and bioinformatics studies have shown that E1B-55k, which is specific to mammalian mastadenoviruses, has evolved by exaptation from an LH3-like minor capsid protein encoded by atadenoviruses. [14]

See also

Related Research Articles

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p53, also known as Tumor protein P53, cellular tumor antigen p53, or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins are crucial in vertebrates, where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.

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<span class="mw-page-title-main">Mdm2</span> Protein-coding gene in the species Homo sapiens

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p21

p21Cip1, also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated with inhibition of CDK2. p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.

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<span class="mw-page-title-main">Bcl-2 homologous antagonist killer</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">BNIP3</span> Protein-coding gene in the species Homo sapiens

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 is a protein found in humans that is encoded by the BNIP3 gene.

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

F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC gene.

<span class="mw-page-title-main">CUL5</span> Protein-coding gene in humans

Cullin-5 is a protein that in humans is encoded by the CUL5 gene.

<span class="mw-page-title-main">HNRPUL1</span> Protein-coding gene in the species Homo sapiens

Heterogeneous nuclear ribonucleoprotein U-like protein 1 is a protein that in humans is encoded by the HNRNPUL1 gene.

<span class="mw-page-title-main">E4F1</span> Protein-coding gene in the species Homo sapiens

Transcription factor E4F1 is a protein that in humans is encoded by the E4F1 gene.

<span class="mw-page-title-main">BNIP3L</span> Protein-coding gene in the species Homo sapiens

BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like is a protein that in humans is encoded by the BNIP3L gene.

<span class="mw-page-title-main">BNIP2</span> Protein-coding gene in the species Homo sapiens

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

Adenovirus genomes are linear, non-segmented double-stranded (ds) DNA molecules that are typically 26-46 Kbp long, containing 23-46 protein-coding genes. The example used for the following description is Human adenovirus E, a mastadenovirus with a 36 Kbp genome containing 38 protein-coding genes. While the precise number and identity of genes varies among adenoviruses, the basic principles of genome organization and the functions of most of the genes described in this article are shared among all adenoviruses.

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

References

  1. ↑ Lowe, SW; Ruley, HE (1993). "Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis". Genes & Development. 7 (4): 535–545. doi: 10.1101/gad.7.4.535 . PMID   8384579.
  2. ↑ White, E; Cipriani, R (January 10, 1990). "Role of adenovirus E1B proteins in transformation: altered organization of intermediate filaments in transformed cells that express the 19-kilodalton protein". Molecular Cell Biology. 10 (1): 120–130. doi:10.1128/MCB.10.1.120. PMC   360719 . PMID   2136765.
  3. 1 2 3 White, Eileen (2001). "Regulation of the cell cycle and apoptosis by the oncogenes of adenovirus". Oncogene. 20 (54): 7836–7846. doi: 10.1038/sj.onc.1204861 . PMID   11753666.
  4. 1 2 Cuconati, Andrea; Chandreyee, Mukherjee; Perez, Denise; White, Eileen (2003). "DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells". Genes & Development. 17 (23): 2922–2932. doi:10.1101/gad.1156903. PMC   289151 . PMID   14633975.
  5. ↑ White, E; Cuconati, A (2002). "Viral homologs of BCL-2: role of apoptosis in the regulation of virus infection". Genes & Development. 16 (19): 2465–2478. doi: 10.1101/gad.1012702 . PMID   12368257.
  6. ↑ Cory, Suzanne; Huang, David; Adams, Jerry (2003). "The Bcl-2 family: roles in cell survival and oncogenesis". Oncogene. 22 (53): 8590–8607. doi: 10.1038/sj.onc.1207102 . PMID   14634621.
  7. ↑ Debbas, M; White, E (April 1993). "Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B". Genes & Development. 7 (4): 546–554. doi: 10.1101/gad.7.4.546 . PMID   8384580.
  8. ↑ Martin, ME; Berk, AJ (1998). "Adenovirus E1B 55k represses p53 activation in vitro". Journal of Virology. 72 (4): 3146–3154. doi:10.1128/JVI.72.4.3146-3154.1998. PMC   109770 . PMID   9525640.
  9. 1 2 Berk, Arnold (2005). "Recent lessons in gene expression, cell cycle control, and cell biology from adenovirus". Oncogene. 24 (52): 7673–7685. doi: 10.1038/sj.onc.1209040 . PMID   16299528.
  10. ↑ Sarnow, P; Hearing, P; Anderson, CW; Halbert, DN; Shenk, T; Levine, AJ (1984). "Adenovirus early region 1B 58,000-dalton tumor antigen is physically associated with an early region 4 25,000-dalton protein in productively infected cells". Journal of Virology. 49 (3): 692–700. doi:10.1128/JVI.49.3.692-700.1984. PMC   255526 . PMID   6699935.
  11. 1 2 Querido, Emmanuelle; Blanchette, Paola; Yan, Qin; Kamura, Takumi; Morrison, Megan; Boivin, Dominique; Kaelin, William; Conaway, Ronald; Conaway, Joan; Branton, Philip (2001). "Degradation of p53 by adenovirus E4orf6 and E1B55k proteins occurs via a novel mechanism involving a Cullin-containing complex". Genes & Development. 15 (23): 3104–3117. doi:10.1101/gad.926401. PMC   312842 . PMID   11731475.
  12. ↑ Stracker, Travis; Carson, Christian; Weitzman, Matthew (2002). "Adenovirus oncoproteins inactivate the Mre11-RAd50-NBS1 DNA repair complex". Nature. 418 (6895): 348–352. Bibcode:2002Natur.418..348S. doi:10.1038/nature00863. PMID   12124628. S2CID   4413110.
  13. ↑ Weiden, MD; Ginsberg, HS (1994). "Deletion of the E4 region of the genome produces adenovirus concatemers". PNAS. 91 (1): 153–157. Bibcode:1994PNAS...91..153W. doi: 10.1073/pnas.91.1.153 . PMC   42904 . PMID   8278357.
  14. ↑ Marabini, R; Condezo, GN; Krupovic, M; Menéndez-Conejero, R; Gómez-Blanco, J; San Martín, C (2021). "Near-atomic structure of an atadenovirus reveals a conserved capsid-binding motif and intergenera variations in cementing proteins". Science Advances. 7 (14): eabe6008. Bibcode:2021SciA....7.6008M. doi:10.1126/sciadv.abe6008. PMC   8011978 . PMID   33789897.
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