Adenovirus E1B protein
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 concatomers of randomly assorted genomes.[13]
See also
References
- ^ 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.
- ^ 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.
- ^ 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. PMID 11753666.
- ^ 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 (23): 2922–2932. doi:10.1101/gad.1156903. PMC 289151. PMID 14633975.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ a b 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.
- ^ 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.
- ^ 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 (23): 3104–3117. doi:10.1101/gad.926401. PMC 312842. PMID 11731475.
- ^ 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.
- ^ 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.