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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.Cite error: The <ref> tag has too many names (see the help page).[1]

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.[2] E1B-19k mimics MCL1, which is a cellular antiapoptotic protein.[3] In infected cells, the expression of E1A results in the degradation of MCL-1, which normally binds the propaptotic protein, BAK.[3] 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.[2][4] This and other proteins released from the mitochondria lead to activation of caspase-9 and caspase-3 and the resulting apoptotic program.[5] However, in adenovirus-infected cells, activated BAK and BAX are sequestered by E1B-19k, preventing the pathway.[2]

E1B-55k

E1B-55k blocks p53 from inhibiting cell cycling and stops it from inducing apoptosis.[6] 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.[7] Presumably, this increased affinity and concentration of p53 turns the p53-E1B-55k complex into a powerful repressor.[8]

E1B-55k also forms a complex with E4orf6, a viral protein.[9] The E1B-55k/E4orf6 complex in infected cells assembles with other cellular proteins to form a ubiquitin ligase complex.[10] Essentially, the E1B-55k/E4orf6 complex takes over the cellular ubiquitin ligase complexes and gives them viral substrate-recognition subunits.[8] There are two known substrates for this ubiquitin ligases; p53 and the MRN complex.[10][11] 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 concatomers of randomly assorted genomes.[12]

See also

References

  1. ^ 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.
  2. ^ a b c 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.
  3. ^ a b 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: 2922–2932. doi:10.1101/gad.1156903. PMC 289151. PMID 14633975.
  4. ^ 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.
  5. ^ Cory, Suzanne; Huang, David; Adams, Jerry (2003). "The Bcl-2 family: roles in cell survival and oncogenesis". Oncogene. 22: 8590–8607. doi:10.1038/sj.onc.1207102.
  6. ^ 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.
  7. ^ Martin, ME; Berk, AJ (1998). "Adenovirus E1B 55k represses p53 activation in vitro". Journal of Virology. 72 (4): 3146–3154. PMC 109770. PMID 9525640.
  8. ^ a b Berk, Arnold (2005). "Recent lessons in gene expression, cell cycle control, and cell biology from adenovirus". Oncogene. 24: 7673–7685. doi:10.1038/sj.onc.1209040. PMID 16299528.
  9. ^ 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. PMC 255526. PMID 6699935.
  10. ^ a b 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: 3104–3117. doi:10.1101/gad.926401. PMC 312842. PMID 11731475.
  11. ^ Stracker, Travis; Carson, Christian; Weitzman, Matthew (2002). "Adenovirus oncoproteins inactivate the Mre11-RAd50-NBS1 DNA repair complex". Nature. 418: 348–352. doi:10.1038/nature00863.
  12. ^ Weiden, MD; Ginsberg, HS (1994). "Deletion of the E4 region of the genome produces adenovirus concatemers". PNAS. 91 (1): 153–157. doi:10.1073/pnas.91.1.153. PMC 42904. PMID 8278357.
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