Page 223 - Avian Virology: Current Research and Future Trends

216 | Zheng

applications of protein–protein interaction screening techniques response to the infection since it inhibited the virus replication
such as yeast two-hybrid screening and immunoprecipitation (Hu et al., 2015). On the contrary, a recent study shows that
assays, the interaction of viral components with cellular proteins IBDV subverted autophagic vacuoles to promote viral maturation
in different pathways regarding apoptosis and cytokine expres- and release (Wang et al., 2017), suggesting that IBDV may take
sion are found at protein levels and shown as follows. advantage of autophagy for its own benefit. Further investiga-
VP1, a RNA-dependent RNA polymerase (RdRp) and tion will be required to elucidate the exact role of VP2-mediated
genome-linked protein of IBDV (von Einem et al., 2004), is autophagy in host response to IBDV infection.
involved in the efficiency of viral replication and modulates the VP3, a scaffold protein of IBDV, interacts with the structural
virulence (Liu and Vakharia, 2004; Wang et al., 2013; Yu et al., protein VP2 and recruits genome dsRNA and VP1 to form a
2013). VP1 interacts with carboxy-terminal domain of transla- ribonucleoprotein (RNP) complex, serving as a transcriptional
tional eukaryotic initiation factor (eif) 4AII, a host translation activator (Lombardo et al., 1999; Tacken et al., 2002; Ferrero et
initiation factor (Tacken et al., 2004). Recently, it was found al., 2015). It plays a critical role in virus assembly. It is reported
that IBDV infection enhanced eIF4AII expression and that that VP3 shows a higher affinity than MDA5 at binding IBDV
ectopically expressed eIF4AII markedly inhibited IBDV growth genomic dsRNA to evade innate immunity (Ye et al., 2014) (Fig.
in DF1 cells while knockdown of eIF4AII by small interfering 7.3). Besides, VP3 plays a central role in ensuring the viability of
RNA significantly enhanced viral replication in CEF cells (Gao the IBDV replication cycle by preventing PKR-mediated apop-
et al., 2017), indicating an inhibitory role of eIF4AII in IBDV tosis (Busnadiego et al., 2012). Furthermore, the host cellular
replication via interaction with VP1 and suppression of its RNA ribosomal protein L4 (RPL4) was identified as an interacting
polymerase activity. VP1 also interacts with cellular nuclear factor partner of VP3 protein and involved in the modulation of IBDV
45 (NF45), an RNA binding protein that regulates gene expres- replication (Chen et al., 2016). Interestingly, a recent publication
sion, and interaction of NF45 with VP1 inhibits IBDV replication shows that VP3 enhances type I interferon expression and sup-
(Stricker et al., 2010). It seems that the reduction of RNA poly- presses IBDV replication via interacting with chicken Ribosomal
merase activity of VP1 by cellular factors (eIF4AII, NF45) is one Protein L18 (chRPL18), and that VP3, chRPL18 and chPKR
of the strategies employed by host cell to harness viral replication. form a complex affecting viral replication (Wang et al., 2018a).
Thus, it is highly possible to attenuate IBDV strains for vaccine It seems that VP3 facilitates IBDV replication in host cells, but
development via reduction of VP1 RNA polymerase activity. at the same time it is also recognized and interacts with cellular
VP2, a structural protein of IBDV, acts as a viral ligand bind- proteins triggering cell immune response to IBDV infection,
ing to the receptor on host cell membrane for virus attachment, which represents the dual roles of viral components as a result of
which is the initial step of IBDV infection. After IBDV infection, the pathogen–host interaction.
the expression of VP2 in host cell allows it to interact with cellular VP4, known as a non-structural protein and a viral protease
protein for its own benefit. VP2 is the first identified apoptotic to cleave the polyprotein, often exists in the form of tubules (24
inducer in IBDV infected cells, exhibiting cytotoxicity in host to 26 nm in diameter) when expressed in host cells, but it is not
cells and a variety of mammalian cell lines as well (Fernández- a part of the viral particle (Granzow et al., 1997). In addition
Arias et al., 1997), but it has not been found until recently that to the enzymatic activities of VP4 as a viral protease as above
VP2 induces apoptosis via triggering cellular Oral Cancer Over- described, it acts as an essential viral component to suppress type
expressed 1 (ORAOV1) degradation (Qin et al., 2017). Using I interferon expression via binding to Glucocorticoid-induced
yeast two-hybrid screening, immunoprecipitation and confocal leucine zipper (GILZ) (Li et al., 2013), a cellular factor that
microscopy assays, Qin et al. (2017) show that VP2-induced serves as a mediator of the anti-inflammatory effects of gluco-
apoptosis during IBDV infection is mediated by interacting with corticoids (Ayroldi and Riccardi, 2009; Ronchetti et al., 2015).
and reducing ORAOV1, a protein that acts as an antiapoptotic As GILZ interacts and inhibits the activation of nuclear factor
molecule in host cells. It seems that IBDV might take advantage kappa enhancer binding protein (NF-κB) and IL-2 synthesis
of VP2-induced apoptosis via degrading ORAOV1 to facilitate its (Di Marco et al., 2007), it is very likely that IBDV VP4 inhibits
release. However, expression of VP2 in cells triggers autophagy cell immune response via interaction with GILZ, suppressing
(Hu et al., 2015), a physiological process controlled by mecha- NF-κB-mediated signalling pathway. As type I interferon expres-
nistic target of rapamycin (MTOR) kinase-dependent signalling sion is regulated by transcriptional regulator NF-κB and plays an
pathway and closely connected to the innate immunity (He and important role in innate immune response (Wang et al., 2010),
Klionsky, 2009; Puleston and Simon, 2014). It was reported that VP4-induced suppression of the type I interferon response might
the interaction of VP2 with virus receptor heat shock protein result from the inhibitory effect of VP4 on the activation of NF-κB
90 (HSP90AA1) was able to trigger the autophagy directly via via GILZ, which contributes to the immunosuppression of IBDV.
AKT-MTOR pathway (Hu et al., 2015). VP2 interfered with the Further investigation indicates that IBDV VP4 suppresses GILZ
binding between the cytoplasmic HSP90AA1 and AKT, which is degradation by inhibiting K48-linked ubiquitylation of GILZ,
important to maintain the AKT kinase activity (Sato et al., 2000). allowing the accumulation of GILZ for interacting and inhibiting
The disassociation of phosphorylated AKT from HSP90AA1 was the activation of NF-κB, and importantly the inhibition of IFN-β
found to be responsible for dephosphorylation of MTOR which expression by VP4 was associated with the suppression of GILZ
then activated autophagosome formation. Thus, the autophagy ubiquitylation (He et al., 2018). Thus, the mechanism of VP4-
triggered by IBDV was proposed to be the host defensive mediated suppression of type I interferon expression seems to be