2.1 Cell–Cell
Junctions
Many cellular proteins including PDZ domains regulate the formation of membrane junctions which are located at points of cell–cell
contact. There are three types of cell–cell junctions: tight junctions
(TJ), adherens junctions (AJ), and desmosomes. Of the three, TJs
are the most targeted by viral PBMs and they have an important
role maintaining epithelial integrity by creating a barrier to diffusion of solutes across cellular membranes in order to maintain
homeostasis in tissues and organs. Structurally, they are formed by
transmembrane proteins which establish the contact between cells
through their extracellular domains also called tight junction proteins, and by the junctional plaque, which is the complex of intracellular proteins that act as adaptors mediating the interaction of
the cytoplasmic domains of the TJ proteins with the cytoskeleton,
leading to a “tight” interaction between both cells [25]. Cellular
proteins including PDZ domains such as MAGI-I, PATJ, or
MUPP1 are some of these adaptor proteins that are targeted by
the PBMs of different kinds of viruses [25]. These are some of the
most relevant examples.
Adenovirus type 9 (Ad9) is a human virus associated with
benign eye infections that may also cause mammary tumors in
experimental rats [26, 27]. Most human adenovirus infections
lead to carcinogenesis by the products of their genes E1A and
E1B, however Ad9 solely depends on the presence of a PBM in
protein E4-ORF1 to promote cell transformation [28]. This protein has a type I PBM in its carboxy terminal (-ATLV COOH ) that
binds four cellular proteins including PDZ domains that are
involved in establishing TJs: MUPP1, ZO-2, MAGI-1, and PATJ
[29–32]. These interactions lead to the sequestration and consequent inactivation of the four proteins, contributing to the disruption of TJs, one of the hallmarks of carcinogenesis.
HPV E6 protein has a class I PBM (-ETQL COOH ). This protein
forms complexes with the cellular proteins including PDZs and
E6AP ubiquitin ligase promoting the proteasome-mediated degradation of most of the cellular PDZ proteins interacting with E6
PBM. This viral protein also targets many cellular proteins including PDZ domains that contribute to TJ formation as PATJ,
MUPP1, MAGI-1 [29, 32, 33] [34]. However, instead of relocalizing the cellular proteins as Ad9 E4-ORF1 did, HPV E6 promotes
TJ disruption by targeting these proteins for degradation leading to
tumor formation.
Influenza A virus (IAV) is a respiratory virus that affects birds
and mammals. It encodes protein NS1, which is a virulence factor,
whose main function is to counteract the innate immune system
antiviral mechanisms. This protein has a class I PBM in its carboxy
terminus with a sequence that changes in isolates from different
species: in highly pathogenic avian viruses the consensus sequence
is -ESEV COOH , while in less pathogenic human viruses PBM
sequence is -RSKV COOH . Each of these sequences have different
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Junctions
Many cellular proteins including PDZ domains regulate the formation of membrane junctions which are located at points of cell–cell
contact. There are three types of cell–cell junctions: tight junctions
(TJ), adherens junctions (AJ), and desmosomes. Of the three, TJs
are the most targeted by viral PBMs and they have an important
role maintaining epithelial integrity by creating a barrier to diffusion of solutes across cellular membranes in order to maintain
homeostasis in tissues and organs. Structurally, they are formed by
transmembrane proteins which establish the contact between cells
through their extracellular domains also called tight junction proteins, and by the junctional plaque, which is the complex of intracellular proteins that act as adaptors mediating the interaction of
the cytoplasmic domains of the TJ proteins with the cytoskeleton,
leading to a “tight” interaction between both cells [25]. Cellular
proteins including PDZ domains such as MAGI-I, PATJ, or
MUPP1 are some of these adaptor proteins that are targeted by
the PBMs of different kinds of viruses [25]. These are some of the
most relevant examples.
Adenovirus type 9 (Ad9) is a human virus associated with
benign eye infections that may also cause mammary tumors in
experimental rats [26, 27]. Most human adenovirus infections
lead to carcinogenesis by the products of their genes E1A and
E1B, however Ad9 solely depends on the presence of a PBM in
protein E4-ORF1 to promote cell transformation [28]. This protein has a type I PBM in its carboxy terminal (-ATLV COOH ) that
binds four cellular proteins including PDZ domains that are
involved in establishing TJs: MUPP1, ZO-2, MAGI-1, and PATJ
[29–32]. These interactions lead to the sequestration and consequent inactivation of the four proteins, contributing to the disruption of TJs, one of the hallmarks of carcinogenesis.
HPV E6 protein has a class I PBM (-ETQL COOH ). This protein
forms complexes with the cellular proteins including PDZs and
E6AP ubiquitin ligase promoting the proteasome-mediated degradation of most of the cellular PDZ proteins interacting with E6
PBM. This viral protein also targets many cellular proteins including PDZ domains that contribute to TJ formation as PATJ,
MUPP1, MAGI-1 [29, 32, 33] [34]. However, instead of relocalizing the cellular proteins as Ad9 E4-ORF1 did, HPV E6 promotes
TJ disruption by targeting these proteins for degradation leading to
tumor formation.
Influenza A virus (IAV) is a respiratory virus that affects birds
and mammals. It encodes protein NS1, which is a virulence factor,
whose main function is to counteract the innate immune system
antiviral mechanisms. This protein has a class I PBM in its carboxy
terminus with a sequence that changes in isolates from different
species: in highly pathogenic avian viruses the consensus sequence
is -ESEV COOH , while in less pathogenic human viruses PBM
sequence is -RSKV COOH . Each of these sequences have different
222
Carlos Castan ˜ o-Rodriguez et al.