1. nuclear bodies, where the 4E-sensitivity element

1. What are the functions of eIF4E in eukaryotes and what
is involved in these functions?

A cap-dependent mechanism is used to mediate most of the
initiations of translation. The cap-binding complex recognizes the cap
structure which is at the 5′ end of cytoplasmic mRNA and binds to it.  eIF4A and eIF4G (RNA helicase) are required
for the binding of mRNA to 40S subunits via the interaction with eIF3. A 43s
pre-initiation complex on the mRNA is then formed. Other initiation factors
such as eIF1 and eIF1A are also required to recognize the initiation codon. 48s
initiation complex is formed as soon as the initiation codon is located.
Binding of this 48s complex to 60s complex will allow the 80s complex to be
formed and release the initiation factors from the ribosome. In plant cells,
another complex called eIF4F can also be identified, which is composed of eIF4G
and eIF4E. The interaction of eukaryotic mRNA with the eIF4F complex helps the
binding of mRNA to 40S subunits via the interaction with eIF3. The interaction
of eIF4F with eukaryotic mRNA also maintain the mRNA stability via interaction
with the eIF4G and the PABP(PolyA binding protein). The interaction of eIF4G
and PolyA binding protein allows the circularization of mRNA.

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In a site called nuclear bodies, where the 4E-sensitivity
element is released, approximately 68% of eIF4E is found. 4E-transporters will
bind to the eIF4E, which helps it enter the nucleus. Interaction of eIF4E and
homeodomain proteins occur once eIF4E enter the nucleus, by binding to them,
cap-binding can be regulated, and mRNA will be inhibited. An example of
homeodomain protein is PML (promyelocytic leukaemia protein), which regulates
eIF4E mRNA transport when a stress occurs, e.g. virus infection. The binding of
PML to eIF4E will inhibit the cap-4E interactions. There are about 200
homeodomain proteins containing eIF4E-binding site, it is thought that they are
all involved in the regulation of eIF4E.

 

Positive-stranded RNA viruses such as caliciviruses use a
novel mechanism for the initiation of translation. The calicivirus mRNA is
covalently bound to the VPg(viral protein) where this VPg can recruit eIF4E.
The interaction of VPg and eIF4E is different in mammalian RNA viruses, where
in potyvirus mRNAs, similar interaction occurred. Therefore, even the function
of different VPg directed translation is the same, the way how eIF4E interact
with the viral protein may be different.

 

eIF4E may also plays an essential role in the formation
of memory, as it is involved in the changes of synaptic connections between
neurons. It has also been suggesting that eIF4E could also mediate aging. In an
experiment, the life-span of the Caenorhabditis elegans were increased when its
eIF4E isoform were knockdown.

 

 

 

 

 

 

 

 

 

 

 

 

 

2. What is the importance of eIF4E for certain mammalian
and plant viruses and what is involved in these processes?

Binding of the viral protein of several potyviruses to
the eIF4E or to its isoform has been observed in vitro binding assays. When
there is a mutation in VPg which suppress the interaction with eIF4E, the viral
infection is prevented. This indicates the interaction of VPg and eIF4E play a
key role in the virus cell cycle.

Mutations of eIF4E may result in resistance to
potyviruses, e.g. pot-1 gene for tomato resistance to TEV. The mutated gene
results in a few amino acid changes in the eIF4E protein. However, not all the
potyruses will be affected, as they may have a different ability to use eIF4E
isoforms, an example is the knockout mutation of the Arabidopsis thaliana eIF4E
gene, resistance of LMV and TEV are gained but not CIYVV (Clover yellow vein
virus). Some potyviruses may require only one isoform of eIF4E, other may
require several isoforms. Furthermore, the same potyvirus strain will not use
the same isoform of eIF4E when infecting a different host plants. For example,
the infection of Arabidopsis is depended on eIF?iso?4E of TEV, where the same
stain will depend on eIF4E to infect pepper.

 The interaction of
eIF4E and vital proteins may also be involved in the genome replication.
Uridylated VPg act as a primer for complementary strand synthesis in a replication
model of the picorna like viruses. Through the binding with eIF4G, eIF4E may
have a close contact with PABP, so the viral protein may be positioned near the
viral polyA as it interacts with eIF4E to mediate initiation of RNA
replication.

 

 

3. What opportunities do you see for exploiting eIF4E in
human healthcare?

eIF4E plays an essential role
in the life cycle of many important pathogens, therefore modulating the
activity of eIF4E activity may suppress the growth of pathogens and could be a
possible treatment for viral diseases.  

 

When eIF4E is overexpressed, it may function as an
oncogene. Therefore, regulating eIF4E may be a potential anticancer approach.
Inhibitory protein 4E-BPs (4E-binding proteins) can negatively regulate eIF4E,
it does this by binding to the same binding site for eIF4G. When 4E-BPs is
phosphorylated, it will be released from eIF4E, which allows eIF4G binds to
eIF4E, hence the formation of eIF4F. Treatment using rapamycin and inhibitor of
mTOR allows 4E-BPs to be hypophosphorylated, which then bind strongly to the
eIF4E, preventing the formation of eIF4F, hence the inhibition of cap-dependent
translation.

4EGI-1 and 4EGI-1A were identified by carrying a high
throughput fluorescence polarization-binding assay, both compounds cause the
eIF4G to be released from the eIF4E. Again, inhibiting cap-dependent
translation. Inhibition of A549 lung cancer cells has been observed by the
treatment with 4EGI-1. 4EGI-1 also promote the binding of 4E-BPs to eIF4E.

 

Overexpressing of eIF4E may also increase translation of
neuroligins, which are postsynaptic proteins that leads to an abnormal increase
in excitatory synaptic function and causing ASD-like phenotypes. By preventing
eIF4G binding to eIF4E, the neuroligin protein levels will be reduced.
Inhibitor 4EGI-1 can also be used as a pharmacological rescue of ASD-like
phenotypes. 4EGI-1 will reduce eIF4F activity to wild-type level, rescue the
E/I imbalance phenotype restores the L-LTP threshold.