Biomedical Engineering Reference
In-Depth Information
O
-
O
-
-
O
-
O
P
O
P
O
O
O
CH
2
CH
2
5
5
Base
Base
O
O
4
1
4
1
3
2
3
2
HO
O
O
OH
-
O
-
O
P
O
O
P
O
O
CH
2
CH
2
Base
Base
O
O
HO
O
O
OH
-
O
O
P
-
O
P
O
O
O
(a)
(b)
Figure 8.5
(a) Structural detail of the 2
-5
oligonucleotides (2
-5
A
n
) generated by 2
-5
A
n
synthetase.
Compare the 2
-5
phosphodiester linkages with the 3
-5
linkages characteristic of normal cellular oligonu-
cleotides such as mRNA (b)
Exposure of cells to interferon normally results in the induction of a protein kinase termed
eIF-2
protein kinase. The enzyme, which is synthesized in a catalytically inactive form, is acti-
vated by exposure to dsRNA. The activated kinase then phosplorylates its substrate, i.e. eIF-2
α
,
which is the smallest subunit of initiation factor 2 (eIF
2
). This, in turn, blocks construction of
the smaller ribosomal subunit, thereby preventing translation of all viral (and cellular) mRNA
(Figure 8.6).
Induction of eIF-2
α
α
protein kinase is dependent upon both interferon type and cell type.
are all known to induce the enzyme in various animal cells. However, in
human epithelial cells the kinase is induced only by type I interferons, whereas none of the
interferons seem capable of inducing synthesis of the enzyme in human fi broblasts. The purifi ed
kinase is highly selective for initiation factor eIF-2, which it phosphorylates at a specifi c serine
residue.
Interferon, in particular type I interferon, is well adapted to its antiviral function. Upon entry
into the body, viral particles are likely to encounter IFN-
IFN-
α
, -
β
and -
γ
-producing cells quickly, including
macrophages and monocytes. This prompts interferon synthesis and release. These cells act like
α
/
β
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