PDZ binding properties [22]. The avian virulent PBM binds PDZ
proteins Scribble and Dlg1 [22]. Both proteins promote the assembly and stability of TJs through their interaction with proteins that
are part of the junctional plaque [35, 36]. It was observed that in
the context of the infection of an IAV including an NS1 protein
with the -ESEV PBM, the viral PBM sequestered Dlg1 and Scribble
to perinuclear puncta through a PBM–PDZ interaction disrupting
TJs structurally and functionally [37]. However, its effect on virus
pathogenesis is still to be described.
Flaviviruses Dengue Virus (DV), West Nile Virus (WNV) and
Tick-Borne Encephalitis Virus (TBEV) interact with ZO-1 and
ZO-2 through their carboxy terminus PBM with an unknown
effect [21, 38].
2.2 Cell Polarity
Cell polarity is a phenomenon characterized by an asymmetrical
distribution of biomolecules within the cells such as lipids, proteins,
or an asymmetrical distribution of the cell itself by forming specific
membrane domains, enriching organelles or the cytoskeleton at
specific sites [39]. Cell polarity can be apicobasal, as in epithelial
cells located in a multicellular sheet, including an apical membrane
and a basolateral membrane; anterior–posterior, as in the case of
migrating cells and planar cell polarity, which is developed within
the plane of a given tissue. This phenomenon is required for the
development of the organism and to maintain homeostasis, which
is why a deregulation of cell polarity may lead to tumorigenesis,
several birth defects [40] or diseases [41, 42].
Many cellular proteins including PDZ domains are relevant in
regulating cell polarity [5]. Apical-basal cell polarity is disrupted by
viral PBMs through the interaction with at least one of this three
conserved protein complexes involving proteins with a PDZ
domain: the Apical Crumbs complex involving PATJ-PALS1CRUMBS [43]; the TJ Par Complex involving PAR3-PAR6aPKC [44] and the Lateral Scribble Complex located at more
basal location including Dlg1-Lgl-Scribble [45]. These are some
of the most relevant examples of viral PBMs targeting apical-basal
cell polarity.
Oncovirus such as adenovirus E4-ORF1 and HPV-16 E6 protein PBMs interact and relocalize or eliminate PATJ disrupting the
Apical Crumbs complex leading to the loss of apical-basal polarity,
which promotes cell transformation [32]. HPV E6 PBM also targets the Lateral Scribble Complex such as Scribble and Dlg1 and
promotes their degradation [18, 46]. The consequence of this
degradation in cell polarity has not been fully studied but it could
contribute to tumorigenesis, as there are cervical cancers in which
Dlg1 and Scribble show a reduced expression or are absent
[47]. Human T Cell Leukemia Virus 1 (HTLV-1) Tax protein
includes a PBM in its carboxy terminus (-ETEV COOH ) which is
relevant for virus-induced leukemia. This PBM binds Scribble
PBM-PDZ Interactions and Viral Pathogenesis
223
proteins Scribble and Dlg1 [22]. Both proteins promote the assembly and stability of TJs through their interaction with proteins that
are part of the junctional plaque [35, 36]. It was observed that in
the context of the infection of an IAV including an NS1 protein
with the -ESEV PBM, the viral PBM sequestered Dlg1 and Scribble
to perinuclear puncta through a PBM–PDZ interaction disrupting
TJs structurally and functionally [37]. However, its effect on virus
pathogenesis is still to be described.
Flaviviruses Dengue Virus (DV), West Nile Virus (WNV) and
Tick-Borne Encephalitis Virus (TBEV) interact with ZO-1 and
ZO-2 through their carboxy terminus PBM with an unknown
effect [21, 38].
2.2 Cell Polarity
Cell polarity is a phenomenon characterized by an asymmetrical
distribution of biomolecules within the cells such as lipids, proteins,
or an asymmetrical distribution of the cell itself by forming specific
membrane domains, enriching organelles or the cytoskeleton at
specific sites [39]. Cell polarity can be apicobasal, as in epithelial
cells located in a multicellular sheet, including an apical membrane
and a basolateral membrane; anterior–posterior, as in the case of
migrating cells and planar cell polarity, which is developed within
the plane of a given tissue. This phenomenon is required for the
development of the organism and to maintain homeostasis, which
is why a deregulation of cell polarity may lead to tumorigenesis,
several birth defects [40] or diseases [41, 42].
Many cellular proteins including PDZ domains are relevant in
regulating cell polarity [5]. Apical-basal cell polarity is disrupted by
viral PBMs through the interaction with at least one of this three
conserved protein complexes involving proteins with a PDZ
domain: the Apical Crumbs complex involving PATJ-PALS1CRUMBS [43]; the TJ Par Complex involving PAR3-PAR6aPKC [44] and the Lateral Scribble Complex located at more
basal location including Dlg1-Lgl-Scribble [45]. These are some
of the most relevant examples of viral PBMs targeting apical-basal
cell polarity.
Oncovirus such as adenovirus E4-ORF1 and HPV-16 E6 protein PBMs interact and relocalize or eliminate PATJ disrupting the
Apical Crumbs complex leading to the loss of apical-basal polarity,
which promotes cell transformation [32]. HPV E6 PBM also targets the Lateral Scribble Complex such as Scribble and Dlg1 and
promotes their degradation [18, 46]. The consequence of this
degradation in cell polarity has not been fully studied but it could
contribute to tumorigenesis, as there are cervical cancers in which
Dlg1 and Scribble show a reduced expression or are absent
[47]. Human T Cell Leukemia Virus 1 (HTLV-1) Tax protein
includes a PBM in its carboxy terminus (-ETEV COOH ) which is
relevant for virus-induced leukemia. This PBM binds Scribble
PBM-PDZ Interactions and Viral Pathogenesis
223