leading to perturbations in the cytoskeleton and the loss of T-cell
polarization contributing to tumorigenesis [48, 49].
Cell polarity is also targeted by respiratory viruses such as IAV
and SARS-CoV. In the case of coronaviruses (CoVs), SARS-CoV E
protein, includes a PBM at its carboxy terminus (-DLLV COOH ) that
interacts with the PDZ domain of PALS1. It was observed that this
PBM relocalized PALS1 to the ERGIC in SARS-CoV infected cells,
altering its original localization and disrupting the Apical Crumbs
complex. This activity delayed the formation of TJs between epithelial cells and disrupted cell polarity [50]. IAV NS1 PBM targets
Dlg1 and Scribble as described above, causing the disruption of the
lateral Scribble complex although the physiological consequences
of this disruption have not been clearly established. Both SARSCoV and IAV cause an exacerbated immune response that leads to
lung edema and death in the most severe cases. Edema clearance in
lung epithelia requires proper apico-basal polarity. Therefore, it has
been hypothesized that the disruption of cell polarity of lung
epithelia caused by these viral PBMs could hinder edema clearance
which would lead to edema accumulation and the death of the host.
However, this is yet to be confirmed.
2.3 Cell Survival
and Apoptosis
Viruses inhibit cell apoptosis and enhance cell survival in order to
have a proper environment to replicate. In the case of oncoviruses,
altering cell–cell interactions and cell polarity is part of cell tumorigenesis. However, this is also achieved by their PBMs directly
inhibiting signaling pathways that induce apoptosis and enhancing
those that promote cell survival. Dlg1 and Scribble are well known
for their tumor suppressor activity. Both proteins induce an inhibitory effect on the PI3K-Akt pathway, which upon activation, promotes the phosphorylation of Akt that leads to the activation of
several cellular signaling cascades causing cell proliferation and
survival. Dlg1 interacts with the PBM of cellular protein PTEN
contributing to its activation. PTEN is a phosphatase that acts on
PIP3 leading to the inhibition of the PI3K-Akt pathway. Similarly,
Scribble inhibits this pathway by its interaction with the PBM of the
cellular phosphatase PHLPP [51], localizing PHLPP to the membrane where it exerts its inhibitory effect over the PI3K-Akt pathway. HTLV-1 Tax protein PBM interacts with both Dlg1 and
Scribble competing with PTEN and PHLPP, respectively, contributing to the activation of the PI3K-Akt pathway [52].
Similarly, HPV E6 protein interacts and promotes the degradation of MAGI-2 and MAGI-3 [53], two PDZ proteins which bind
PTEN through its own PBM. It has been hypothesized that HPV
would induce the degradation of MAGI-2 and MAGI-3 leading to
the deregulation of PTEN causing cell malignancy. However, this
effect is yet to be proven experimentally. There are many other
signaling pathways involving cellular PDZ proteins. In this cases,
E6 PBM affects cell proliferation and survival, as reviewed [16].
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Carlos Castan ˜ o-Rodriguez et al.
polarization contributing to tumorigenesis [48, 49].
Cell polarity is also targeted by respiratory viruses such as IAV
and SARS-CoV. In the case of coronaviruses (CoVs), SARS-CoV E
protein, includes a PBM at its carboxy terminus (-DLLV COOH ) that
interacts with the PDZ domain of PALS1. It was observed that this
PBM relocalized PALS1 to the ERGIC in SARS-CoV infected cells,
altering its original localization and disrupting the Apical Crumbs
complex. This activity delayed the formation of TJs between epithelial cells and disrupted cell polarity [50]. IAV NS1 PBM targets
Dlg1 and Scribble as described above, causing the disruption of the
lateral Scribble complex although the physiological consequences
of this disruption have not been clearly established. Both SARSCoV and IAV cause an exacerbated immune response that leads to
lung edema and death in the most severe cases. Edema clearance in
lung epithelia requires proper apico-basal polarity. Therefore, it has
been hypothesized that the disruption of cell polarity of lung
epithelia caused by these viral PBMs could hinder edema clearance
which would lead to edema accumulation and the death of the host.
However, this is yet to be confirmed.
2.3 Cell Survival
and Apoptosis
Viruses inhibit cell apoptosis and enhance cell survival in order to
have a proper environment to replicate. In the case of oncoviruses,
altering cell–cell interactions and cell polarity is part of cell tumorigenesis. However, this is also achieved by their PBMs directly
inhibiting signaling pathways that induce apoptosis and enhancing
those that promote cell survival. Dlg1 and Scribble are well known
for their tumor suppressor activity. Both proteins induce an inhibitory effect on the PI3K-Akt pathway, which upon activation, promotes the phosphorylation of Akt that leads to the activation of
several cellular signaling cascades causing cell proliferation and
survival. Dlg1 interacts with the PBM of cellular protein PTEN
contributing to its activation. PTEN is a phosphatase that acts on
PIP3 leading to the inhibition of the PI3K-Akt pathway. Similarly,
Scribble inhibits this pathway by its interaction with the PBM of the
cellular phosphatase PHLPP [51], localizing PHLPP to the membrane where it exerts its inhibitory effect over the PI3K-Akt pathway. HTLV-1 Tax protein PBM interacts with both Dlg1 and
Scribble competing with PTEN and PHLPP, respectively, contributing to the activation of the PI3K-Akt pathway [52].
Similarly, HPV E6 protein interacts and promotes the degradation of MAGI-2 and MAGI-3 [53], two PDZ proteins which bind
PTEN through its own PBM. It has been hypothesized that HPV
would induce the degradation of MAGI-2 and MAGI-3 leading to
the deregulation of PTEN causing cell malignancy. However, this
effect is yet to be proven experimentally. There are many other
signaling pathways involving cellular PDZ proteins. In this cases,
E6 PBM affects cell proliferation and survival, as reviewed [16].
224
Carlos Castan ˜ o-Rodriguez et al.