Adenovirus E1B protein

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. E1B-19k mimics MCL1, which is a cellular antiapoptotic protein. In infected cells, the expression of E1A results in the degradation of MCL-1, which normally binds the proapoptotic protein, BAK. BAK activation induces apoptosis by co-oligomerizing with another proapoptotic protein, BAX. Together, BAK and BAX form pores in the mitochondrial membrane, releasing apoptogenic proteins like cytochrome c. This and other proteins released from the mitochondria lead to activation of caspase-9 and caspase-3 and the resulting apoptotic program. However, in adenovirus-infected cells, activated BAK and BAX are sequestered by E1B-19k, preventing the pathway.

E1B-55k

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

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

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.

References

References

1. (April 1993). "Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis". Genes & Development.
2. (January 1990). "Role of adenovirus E1B proteins in transformation: altered organization of intermediate filaments in transformed cells that express the 19-kilodalton protein". Molecular and Cellular Biology.
3. (November 2001). "Regulation of the cell cycle and apoptosis by the oncogenes of adenovirus". Oncogene.
4. (December 2003). "DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells". Genes & Development.
5. (October 2002). "Viral homologs of BCL-2: role of apoptosis in the regulation of virus infection". Genes & Development.
6. (November 2003). "The Bcl-2 family: roles in cell survival and oncogenesis". Oncogene.
7. (April 1993). "Wild-type p53 mediates apoptosis by E1A, which is inhibited by E1B". Genes & Development.
8. (April 1998). "Adenovirus E1B 55K represses p53 activation in vitro". Journal of Virology.
9. (November 2005). "Recent lessons in gene expression, cell cycle control, and cell biology from adenovirus". Oncogene.
10. (March 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.
11. (December 2001). "Degradation of p53 by adenovirus E4orf6 and E1B55K proteins occurs via a novel mechanism involving a Cullin-containing complex". Genes & Development.
12. (July 2002). "Adenovirus oncoproteins inactivate the Mre11-Rad50-NBS1 DNA repair complex". Nature.
13. (January 1994). "Deletion of the E4 region of the genome produces adenovirus DNA concatemers". Proceedings of the National Academy of Sciences of the United States of America.
14. (March 2021). "Near-atomic structure of an atadenovirus reveals a conserved capsid-binding motif and intergenera variations in cementing proteins". Science Advances.