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María Ángel García Chaves

Figure 3. PKR induces apoptosis activating both, the extrinsic and the intrinsic routes of caspases activation. Through interaction
with FADD, PKR activates caspase-8, which in turn activates the conversion of Procaspase-3 and provokes Bid/Bax interaction, release
of cytochrome c from the mitochondria and formation of the apoptosome (Apaf-1/cytochrome c/caspase-9). Both pathways result in
activation of caspase-3 and degradation of DNA, thus resulting in programmed cell death or apoptosis.

3. PKR REGULATION phosphatase-1 cofactor PP1c leading to enhanced
dephosphorylation of eIF-2a (77). In addition, some viral
The importance of PKR function in antiviral defence, mRNA could initiate translation in an eIF2-independent
cell growth, differentiation, stress response, and immune manner by means of a dedicated RNA structure that stalls
modulation is further highlighted by the existence of the scanning 40S ribosome on the initiation codon (78).
specific direct and indirect modulators. Viral inhibitors are normally expressed from the onset of
infection to maintain PKR inactive until the virus cycle is
3.1. Viral modulators of PKR effect: E3L from vaccinia completed. Elimination of PKR inhibitors from these
virus, LANA 2 from Kaposi’s sarcoma herpesvirus, and viruses generally has a severe impact on virus replication
polyprotein from hepatitis c virus as subjects of our and pathogenesis. Viruses disarmed of PKR inhibitors
interest usually replicate at lower levels than wild-type viruses in
normal cultured cells, and show an attenuated phenotype
Since the IFN-induced cellular antiviral response is the in animals. A detailed analysis of different viral proteins
primary defence mechanism against virus infections, many inhibiting PKR was made in our reviews in 2006 (1, 2). In
viruses have developed a means to counteract the the present review, an update with new viral proteins is
induction or effects of IFN (1, 2). Viruses use a number of displayed in Table 1. In addition, our contribution to the
strategies to counteract dsRNA-dependent pathways, and study of different viral proteins modulating the PKR effect
specifically to avoid the deleterious effects of the PKR and is also discussed.
other IFN-induced systems. Numerous viral proteins have
been identified as able to avoid the PKR effect, directly Vaccinia virus (VV) and its derivative viruses have
binding PKR or indirectly preventing eIF2a been widely used by the group of Dr Esteban, and are still
phosphorylation. One recently-researched mechanism that being researched as very promising vaccines against
contributes indirectly by inhibiting the effect of PKR is several infections and diseases (HIV, HCV, malaria,
mediated by growth arrest and DNA damage-inducible cancer, etc.) (79). VV is relatively resistant to the antiviral
protein 34 (GADD34), which physically interacts with

150 @Real Academia Nacional de Farmacia. Spain