Biology: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]

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

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. PMID 2136765. 
  3. ↑ 3.0 3.1 3.2 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. ↑ 4.0 4.1 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. 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. http://genesdev.cshlp.org/content/7/4/546.abstract. 
  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. PMID 9525640. 
  9. ↑ 9.0 9.1 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. PMID 6699935. 
  11. ↑ 11.0 11.1 Querido, Emmanuelle; Blanchette, Paola; Yan, Qin; Kamura, Takumi; Morrison, Megan; Boivin, Dominique; Kaelin, William; Conaway, Ronald et al. (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. 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. doi:10.1038/nature00863. PMID 12124628. Bibcode: 2002Natur.418..348S. 
  13. ↑ 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. PMID 8278357. Bibcode: 1994PNAS...91..153W. 
  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. doi:10.1126/sciadv.abe6008. PMID 33789897. Bibcode: 2021SciA....7.6008M. 



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