Adenovirus E1B protein usually refers to one of two
proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
transcribed from the E1B gene of the
adenovirus
Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from the ...
: 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
p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
, a tumor suppressor.
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
Induced myeloid leukemia cell differentiation protein Mcl-1 is a protein that in humans is encoded by the ''MCL1'' gene.
Function
The protein encoded by this gene belongs to the Bcl-2 family. Alternative splicing occurs at this locus and two tr ...
, which is a cellular antiapoptotic protein.
In infected cells, the expression of E1A results in the degradation of MCL-1, which normally binds the propaptotic protein, BAK.
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
The cytochrome complex, or cyt ''c'', is a small hemeprotein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins and plays a major role in cell apoptosis. Cytochrome c is hig ...
.
This and other proteins released from the mitochondria lead to activation of
caspase-9
Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such ...
and
caspase-3
Caspase-3 is a caspase protein that interacts with caspase-8 and caspase-9. It is encoded by the ''CASP3'' gene. ''CASP3'' orthologs have been identified in numerous mammals for which complete genome data are available. Unique orthologs are also p ...
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 (MRX complex in yeast) is a protein complex consisting of Mre11, Rad50 and Nbs1 (also known as Nibrin in humans and as Xrs2 in yeast). In eukaryotes, the MRN/X complex plays an important role in the initial processing of double-st ...
.
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.
Structural and bioinformatics studies have shown that E1B-55k, which is specific to mammalian
mastadenovirus
''Mastadenovirus'' is a genus of viruses in the family ''Adenoviridae''. Humans and other mammals serve as natural hosts. There are 51 species in this genus. The genus as a whole includes many very common causes of human infection, estimated to ...
es, has evolved by
exaptation
Exaptation and the related term co-option describe a shift in the function of a trait during evolution. For example, a trait can evolve because it served one particular function, but subsequently it may come to serve another. Exaptations are common ...
from an LH3-like minor capsid protein encoded by
atadenoviruses.
See also
*
Oncolytic adenovirus
Adenovirus varieties have been explored extensively as a viral vector for gene therapy and also as an oncolytic virus.
Of the many different viruses being explored for oncolytic potential, an adenovirus was the first to be approved by a regulatory ...
References
{{reflist, 30em
Proteins
Adenoviridae