interferon (IFN) signaling in infected cells. TBEV NS5 protein
includes a PBM at its carboxy-terminus and an internal PBM that
binds Scribble [61]. This interaction does not relocalize or inhibit
Scribble’s activity, it just targets NS5 protein to the membrane,
where Scribble is generally located, and contributes to the inhibition of interferon mediated JAK-STAT signaling [61]. However,
the exact mechanism governing this inhibition or the relevance of
this interaction in the context of the viral infection is still to be
elucidated.
Similarly, the PBM–PDZ dependent interaction of IAV NS1
protein with both Dlg1 and Scribble has recently been reported in
APCs [59]. Although the consequence of this interaction in vivo is
still to be elucidated, it suggests a role of IAV NS1 PBM in modifying the host immune response.
In the case of CoVs, our laboratory generated a collection of
recombinant SARS-CoVs with mutations affecting E protein PBM.
Their analysis in vivo showed that SARS-CoV variants missing E
protein PBM were attenuated, indicating that E protein PBM was a
virulence determinant. Then, we described that the interaction of
this viral PBM with the PDZ domains of cellular protein syntenin
during viral infection activated p38 MAPK. This interaction promoted the over expression of proinflammatory cytokines, causing
the death of the host due to a pathogenic immune response
[23]. These data indicated a clear role of PBM–PDZ interaction
in the lung pathology observed in SARS-CoV infected patients.
Both CoV and Flaviviruses infect cells of the immune system,
although in some cases the infection is nonproductive [62–
65]. How the pathology of these viruses is influenced by the
interaction of these viral PBMs with cellular PDZ proteins of
immune cells still needs to be addressed.
3 Relevance of CoVs Proteins Including a PBM
CoVs have several proteins including PBMs binding a set of cellular
PDZs with the potential of influencing cell behavior. Some of these
interactions are reviewed next.
The relevance of SARS-CoV E protein PBM was further supported by the observation that a SARS-CoV attenuated deletion
mutant lacking E protein (SARS-CoV-ΔE), after several passages in
cell culture and in vivo, reverted to a virulent phenotype by incorporating chimeric proteins including new PBMs, thus compensating for the loss of E protein PBM and reinforcing its relevant role in
virus virulence [66].
Also, SARS-CoV 3a protein has a PBM motif in its carboxy
terminus (-SVPL COOH ). However, this PBM is not involved in
virus replication and pathogenesis, in contrast to E protein PBM,
when located in its native protein, implying that either there is a
hierarchy between both PBMs when they are located in their native
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Carlos Castan ˜ o-Rodriguez et al.
includes a PBM at its carboxy-terminus and an internal PBM that
binds Scribble [61]. This interaction does not relocalize or inhibit
Scribble’s activity, it just targets NS5 protein to the membrane,
where Scribble is generally located, and contributes to the inhibition of interferon mediated JAK-STAT signaling [61]. However,
the exact mechanism governing this inhibition or the relevance of
this interaction in the context of the viral infection is still to be
elucidated.
Similarly, the PBM–PDZ dependent interaction of IAV NS1
protein with both Dlg1 and Scribble has recently been reported in
APCs [59]. Although the consequence of this interaction in vivo is
still to be elucidated, it suggests a role of IAV NS1 PBM in modifying the host immune response.
In the case of CoVs, our laboratory generated a collection of
recombinant SARS-CoVs with mutations affecting E protein PBM.
Their analysis in vivo showed that SARS-CoV variants missing E
protein PBM were attenuated, indicating that E protein PBM was a
virulence determinant. Then, we described that the interaction of
this viral PBM with the PDZ domains of cellular protein syntenin
during viral infection activated p38 MAPK. This interaction promoted the over expression of proinflammatory cytokines, causing
the death of the host due to a pathogenic immune response
[23]. These data indicated a clear role of PBM–PDZ interaction
in the lung pathology observed in SARS-CoV infected patients.
Both CoV and Flaviviruses infect cells of the immune system,
although in some cases the infection is nonproductive [62–
65]. How the pathology of these viruses is influenced by the
interaction of these viral PBMs with cellular PDZ proteins of
immune cells still needs to be addressed.
3 Relevance of CoVs Proteins Including a PBM
CoVs have several proteins including PBMs binding a set of cellular
PDZs with the potential of influencing cell behavior. Some of these
interactions are reviewed next.
The relevance of SARS-CoV E protein PBM was further supported by the observation that a SARS-CoV attenuated deletion
mutant lacking E protein (SARS-CoV-ΔE), after several passages in
cell culture and in vivo, reverted to a virulent phenotype by incorporating chimeric proteins including new PBMs, thus compensating for the loss of E protein PBM and reinforcing its relevant role in
virus virulence [66].
Also, SARS-CoV 3a protein has a PBM motif in its carboxy
terminus (-SVPL COOH ). However, this PBM is not involved in
virus replication and pathogenesis, in contrast to E protein PBM,
when located in its native protein, implying that either there is a
hierarchy between both PBMs when they are located in their native
226
Carlos Castan ˜ o-Rodriguez et al.