contexts [67] or that the PBM works in collaboration with an
additional motif present in other viral proteins.
Interestingly, when a SARS-CoV variant lacking proteins E and
3a simultaneously was generated, the virus was not viable. In fact,
we described that either E or 3a protein PBM was essential for virus
viability when one of the two proteins was deleted, indicating that
there was a complementation between both viral PBMs [67]. Given
the relevance of SARS-CoV E and 3a protein PBMs, the presence of
PBM motifs in proteins of other CoVs species was reviewed
(Table 2). To date, the PBMs of SARS-CoV E and 3a proteins are
the only CoV PBMs that have been studied in detail.
The relevance of PBMs in other CoV proteins in virus pathogenicity and replications has been determined with limited extent.
Recently in our laboratory, we have shown that MERS-CoV E
protein PBM is also a virulence factor, suggesting that this virus
could trigger a similar virulence mechanism than SARS-CoV
(FJ Gutie ´rrez-A ´ lvarez, Enjuanes, 2020, unpublished results).
Also, the relevance in virus replication and pathogenesis of human
OC43-CoV E protein PBM has been recently proposed
[68]. Another example is FIPV 7b protein, that includes a PBM
that when modified, changes the subcellular localization of the
protein [69]. A new human highly pathogenic coronavirus,
named SARS-CoV-2 [70] emerged in Wuhan in December 2019
and to date it has spread to more than 200 countries with more
than 51.000.000 confirmed cases and causing 1.280.000 deaths
(data from WHO as to 13, November, 2020) leading to an unparalleled global crisis. This new pathogen was analyzed showing 79%
sequence identity to SARS-CoV [71]. Interestingly, this virus has a
3a and E proteins in which the PBM sequence is identical to that of
SARS-CoV, suggesting that these PBMs could be involved in virus
replication and pathogenesis triggering the same cellular pathways
that are activated by SARS-CoV E and 3a protein PBMs. Although
functional studies are required to confirm this hypothesis, SARSCoV-2 PBMs could be a promising target for potential antivirals.
Current theories state that CoVs were originated in bats and
then transmitted to birds generating two branches of CoVs that
were classified in four CoVs genera: Alphacoronavirus and Betacoronavirus, which are derived from bat CoVs and Gammacoronavirus
and Deltacoronavirus, which are derived from bird CoVs
[72]. Forty-three potential PBMs have been identified in
33 CoVs species.
It has been observed that there are more PBMs in CoVs from
genera derived from bat CoVs (Alphacoronavirus and Betacoronavirus) than in those derived from bird CoVs (Gammacoronavirus
and Deltacoronavirus). This suggests that, during CoV evolution,
PBMs were incorporated in CoV genomes earlier in genera Alphacoronavirus and Betacoronavirus. Furthermore, a PBM was identified in the carboxy terminus of the E protein of every analyzed CoV
PBM-PDZ Interactions and Viral Pathogenesis
227
additional motif present in other viral proteins.
Interestingly, when a SARS-CoV variant lacking proteins E and
3a simultaneously was generated, the virus was not viable. In fact,
we described that either E or 3a protein PBM was essential for virus
viability when one of the two proteins was deleted, indicating that
there was a complementation between both viral PBMs [67]. Given
the relevance of SARS-CoV E and 3a protein PBMs, the presence of
PBM motifs in proteins of other CoVs species was reviewed
(Table 2). To date, the PBMs of SARS-CoV E and 3a proteins are
the only CoV PBMs that have been studied in detail.
The relevance of PBMs in other CoV proteins in virus pathogenicity and replications has been determined with limited extent.
Recently in our laboratory, we have shown that MERS-CoV E
protein PBM is also a virulence factor, suggesting that this virus
could trigger a similar virulence mechanism than SARS-CoV
(FJ Gutie ´rrez-A ´ lvarez, Enjuanes, 2020, unpublished results).
Also, the relevance in virus replication and pathogenesis of human
OC43-CoV E protein PBM has been recently proposed
[68]. Another example is FIPV 7b protein, that includes a PBM
that when modified, changes the subcellular localization of the
protein [69]. A new human highly pathogenic coronavirus,
named SARS-CoV-2 [70] emerged in Wuhan in December 2019
and to date it has spread to more than 200 countries with more
than 51.000.000 confirmed cases and causing 1.280.000 deaths
(data from WHO as to 13, November, 2020) leading to an unparalleled global crisis. This new pathogen was analyzed showing 79%
sequence identity to SARS-CoV [71]. Interestingly, this virus has a
3a and E proteins in which the PBM sequence is identical to that of
SARS-CoV, suggesting that these PBMs could be involved in virus
replication and pathogenesis triggering the same cellular pathways
that are activated by SARS-CoV E and 3a protein PBMs. Although
functional studies are required to confirm this hypothesis, SARSCoV-2 PBMs could be a promising target for potential antivirals.
Current theories state that CoVs were originated in bats and
then transmitted to birds generating two branches of CoVs that
were classified in four CoVs genera: Alphacoronavirus and Betacoronavirus, which are derived from bat CoVs and Gammacoronavirus
and Deltacoronavirus, which are derived from bird CoVs
[72]. Forty-three potential PBMs have been identified in
33 CoVs species.
It has been observed that there are more PBMs in CoVs from
genera derived from bat CoVs (Alphacoronavirus and Betacoronavirus) than in those derived from bird CoVs (Gammacoronavirus
and Deltacoronavirus). This suggests that, during CoV evolution,
PBMs were incorporated in CoV genomes earlier in genera Alphacoronavirus and Betacoronavirus. Furthermore, a PBM was identified in the carboxy terminus of the E protein of every analyzed CoV
PBM-PDZ Interactions and Viral Pathogenesis
227