| Encephalomyocarditis virus (EMCV) is an emerging infectious disease
of pigs in Europe. EMCV is a positive sense picornavirus that does not encode any glycoslyated
proteins. It has been known for years that EMCV is very sensitive to interferon but that EMCV
can be rescued from the inhibitory affects of interferon when co-infected with vaccinia virus,
which is interferon-resistant. We have previously demonstrated that the K3L gene of vaccinia
virus is both necessary and sufficient for the rescue of EMCV from the inhibitory affects of
interferon. K3L acts as a psuedo-substrate for the interferon-induced dsRNA-activated eIF2
kinase, protein kinase R (PKR). We have also previously demonstrated that vaccinia virus’
other interferon-inhibitory protein, E3L, cannot rescue EMCV from the inhibitory effects of
interferon. The fact that K3L can rescue EMCV, whereas E3L cannot, generated a conundrum. It
is known that E3L, a dsRNA-binding protein inhibits two of the interferon-induced antiviral
pathways (PKR and 2’5’ oligoadenylate synthetase) while K3L is known to only inhibit PKR. Why
does K3L rescue EMCV and E3L cannot rescue? Here we report that EMCV infection activates an
additional eIF2 kinase, Perk. Perk in known to be activated by misfolded proteins in the rough
endoplasmic recticulum. We also report that K3L inhibits Perk phosphorylation of eIF2.
Furthermore, when Perk expression is diminished with antisense RNA oligos, the interferon-induced
antiviral state against EMCV is reduced by almost 100 fold. Since EMCV does not encode any
glycoslyated proteins, we hypothesize that viral genome replication on the smooth endoplasmic
recticulum is the stimulus which activates Perk. Furthermore both perk and PKR activation is
required for the interferon induced antiviral state. |
