On the other hand, viruses that are highly pathogenic but do
not generate tumors, like Rabies (RABV) or IAV, also interfere with
cellular PDZs affecting cell survival and apoptosis, but with a
different effect. For instance, the interaction of highly pathogenic
avian IAV H7N1 NS1 protein PBM (-ESEV COOH ) with Scribble
led to an increase in viral titers that was not observed in a virus
variant with a mutant PBM (-ESEA COOH ), which did not bind
Scribble. This binding blocked Scribble antiapoptotic function
relocalizing the protein into cytoplasmic puncta, suggesting that
the inhibition of apoptosis by this PBM was responsible for an
increase in virus titers [54]. RABV virus, a neurotropic virus that
causes severe encephalitis in mammals, includes a PBM in the
carboxy terminus end of its G protein. Infections by RABV variants
that promote neuronal death by apoptosis lead to the survival of the
host in contrast to those that promote cell survival, which are highly
virulent [55]. This difference is due to the changes in the sequence
of G protein PBM. Variants that include the PBM -QTRL COOH
bind the PDZ domain of cellular Ser/Thr kinase MAST2 with
similar affinity as its natural binder, PTEN [56]. This leads to the
activation of Akt and therefore, cell survival. In contrast, attenuated
variants include the sequence -ETRL COOH , showing an increased
PDZ binding ability, binding to MAST2 and Dlg2, MUPP1 and
PTPN4, a protein that upon activation, promotes neural apoptosis
overcoming the effect of the binding to MAST2 [55]. Furthermore,
a recent analysis of the sequence of the G protein of high morbidity
and low morbidity RABV variants has revealed that low morbidity
viruses lack a PBM in its carboxy terminus domain, further supporting the implications on pathogenesis on RABV G protein PBM
[57, 58].
2.4 Disruption
of the Immune System
Viral PBMs also subvert the host immune system by triggering or
inhibiting signaling pathways contributing to viral pathogenesis
either by suppressing the immune system or by triggering an exacerbated immune response which is deleterious to the host.
T cells are responsible for adaptative immune response of the
host. The interaction with antigen presenting cells (APC) through
their membrane T-cell receptor (TCR) triggers signaling pathways
that lead to T-cell activation. These pathways are regulated in both
APCs and T-cells by several factors including Dlg1 and Scribble
[59]. One of them, is the Akt pathway, targeted by HTLV-1 Tax
protein, discussed above, as it is also involved in the regulation of
cell proliferation and apoptosis. The interaction of Tax protein
PBM with these proteins inhibits T cell activation, contributing to
the depletion of the adaptative immune response and the survival of
the virus within T-cells.
Also, Flaviviruses and CoVs influence the immune system
through the interaction of their PBMs with cellular PDZs. IFN is
one of the main determinants of host anti-viral response [60] and is
targeted by proteins NS5 from the Flaviviridae family, inhibiting
PBM-PDZ Interactions and Viral Pathogenesis
225
not generate tumors, like Rabies (RABV) or IAV, also interfere with
cellular PDZs affecting cell survival and apoptosis, but with a
different effect. For instance, the interaction of highly pathogenic
avian IAV H7N1 NS1 protein PBM (-ESEV COOH ) with Scribble
led to an increase in viral titers that was not observed in a virus
variant with a mutant PBM (-ESEA COOH ), which did not bind
Scribble. This binding blocked Scribble antiapoptotic function
relocalizing the protein into cytoplasmic puncta, suggesting that
the inhibition of apoptosis by this PBM was responsible for an
increase in virus titers [54]. RABV virus, a neurotropic virus that
causes severe encephalitis in mammals, includes a PBM in the
carboxy terminus end of its G protein. Infections by RABV variants
that promote neuronal death by apoptosis lead to the survival of the
host in contrast to those that promote cell survival, which are highly
virulent [55]. This difference is due to the changes in the sequence
of G protein PBM. Variants that include the PBM -QTRL COOH
bind the PDZ domain of cellular Ser/Thr kinase MAST2 with
similar affinity as its natural binder, PTEN [56]. This leads to the
activation of Akt and therefore, cell survival. In contrast, attenuated
variants include the sequence -ETRL COOH , showing an increased
PDZ binding ability, binding to MAST2 and Dlg2, MUPP1 and
PTPN4, a protein that upon activation, promotes neural apoptosis
overcoming the effect of the binding to MAST2 [55]. Furthermore,
a recent analysis of the sequence of the G protein of high morbidity
and low morbidity RABV variants has revealed that low morbidity
viruses lack a PBM in its carboxy terminus domain, further supporting the implications on pathogenesis on RABV G protein PBM
[57, 58].
2.4 Disruption
of the Immune System
Viral PBMs also subvert the host immune system by triggering or
inhibiting signaling pathways contributing to viral pathogenesis
either by suppressing the immune system or by triggering an exacerbated immune response which is deleterious to the host.
T cells are responsible for adaptative immune response of the
host. The interaction with antigen presenting cells (APC) through
their membrane T-cell receptor (TCR) triggers signaling pathways
that lead to T-cell activation. These pathways are regulated in both
APCs and T-cells by several factors including Dlg1 and Scribble
[59]. One of them, is the Akt pathway, targeted by HTLV-1 Tax
protein, discussed above, as it is also involved in the regulation of
cell proliferation and apoptosis. The interaction of Tax protein
PBM with these proteins inhibits T cell activation, contributing to
the depletion of the adaptative immune response and the survival of
the virus within T-cells.
Also, Flaviviruses and CoVs influence the immune system
through the interaction of their PBMs with cellular PDZs. IFN is
one of the main determinants of host anti-viral response [60] and is
targeted by proteins NS5 from the Flaviviridae family, inhibiting
PBM-PDZ Interactions and Viral Pathogenesis
225