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serine 42
CDK2 phosphorylation site

BR1 BR2 Leucine zipper Transactivation/Repression

1 30 35 62 78 120 339

54 127
20 PLDLS 24 p53 binding region
CtBP interaction motif

Figure 12.3 Schematic representation of MDV Meq protein. Numbers in the figure indicate amino acid residue position.

organs, in vivo (Lupiani et al., 2004). Meq has been shown to vIL8
Figure 3
form homodimer with itself and heterodimer with c-Jun, JunB, MDV vIL8, encoded by MDV003 and MDV078, is a chicken
and Fos, and to bind to specific DNA sequences, called Meq- interleukin-8 homologue. In chickens, 8 CXC chemokine
responsive elements I and II (MERE I and MERE II) (Brown orthologues have been identified thus far. Functions for most of
et al., 2009). Meq-c-Jun heterodimers bind with high affinity to the chicken CXC chemokines except for CXCLi1 and CXCLi2
activator protein 1 (AP-1) like MERE I sites to up-regulate tran- are poorly understood and mostly deduced from mammalian
scription of various gene promoters, including meq, while Meq homologues (Kaiser et al., 2005). The vIL8 is an MDV-1 specific
homodimers bind to MERE II sites and repress the transcription gene which consists of three exons separated by two introns, in
of the bi-directional promoter between pp38 and pp14 (Levy which exon I encodes for the secretory signal peptide, and exons
et al., 2003; Brown et al., 2009). Meq also binds to the MDV II and III contain four conserved cysteine residues typical of
lytic origin of replication, Meq promoter, and ICP4 promoters CXC chemokines. Functionally, and despite being designated
(Levy et al., 2003). In addition to Fos and Jun, Meq interacts an IL8 orthologue, vIL8 shows chemotactic properties for
with several other proteins involved in cell cycle control, like Rb PBMCs in vitro, suggesting that vIL8 could recruit target cells
(retinoblastoma protein), p53 and cyclin-dependent kinase 2 for infection (Parcells et al., 2001). An in vitro assay with purified
(CDK2). Meq also harbours a Pro-Leu-Asp-Leu-Ser (PLDLS) recombinant vIL8 protein, showed that it can attract B cells and
+
+
motif, which binds to the C-terminal-binding protein (CtBP), CD4 CD25 T-cells (Engel et al., 2012). The vIL8 is expressed
and this interaction is essential for Meq oncogenesis (Brown et in both lytic and latent infections (Engel et al., 2012) and dele-
al., 2006). tion of the entire vIL8 gene resulted in reduced viral replication
Meq is a multifunctional protein that plays an essential role in in lymphoid organs, suggesting a role of vIL8 during early lytic
latency and transformation. More recent studies elucidated the replication (Lupiani et al., 2004). In addition, deletion of vIL8
role of Meq in regulating host pathways. In 2012, using a MDV severely affected MDV pathogenesis and significantly reduced
induced lymphoblastoid cell line, and chromatin immunoprecipi- tumour incidence by about 90% in infected chickens, probably
tation followed by 2D LC-MS/MS, Kumar et al. (2012) identified due to limited virus replication in lymphoid organs (Parcells et al.,
31 proteins that interact with Meq further revealing the role of 2001; Lupiani et al., 2004).
Meq in regulating apoptosis, transcription and cell growth. Then, Splice variants have been identified that contain vIL8 exons II
in 2013, using microarray and chromatin immunoprecipitation and III fused to Meq (Meq/vIL8), and to other upstream genes,
sequencing (ChIP-seq), Kung and Cheng explored the genome- including RLORF4 and RLORF5a. The Meq/vIL8 spliced tran-
wide DNA binding of Meq within the chicken genome and its script retains the DNA binding domain and the modified leucine
role in global transcriptional regulation. These studies concluded zipper domain of Meq, along with the mature receptor-binding
that Meq regulates expression of various genes that fall in extra- portion of vIL8 but lacks the transactivation/transrepression
cellular signal-regulated kinase/mitogen-activated protein kinase domain of Meq responsible for its transcriptional modulation
(ERK/MAPK), Jak-STAT, and ErbB pathways that are important (Fig. 12.2). It has been reported that Meq and Meq/vIL8 local-
for oncogenesis and apoptosis (Subramaniam et al., 2013). ize to the nucleoplasm, nucleoli, and Cajal bodies of transfected
Meq is also a polymorphic protein that has several variants, cells (Anobile et al., 2006). In addition, Meq/vIL8 is able to form
including long Meq (L-Meq), short Meq (S-Meq), and very short homodimers and shows distinct mobility patterns that differ from
Meq (VS-Meq), which contain insertions or deletions, but their the pattern of Meq, suggesting that the splice variants may be bio-
role in MDV pathogenesis remain unclear (Deng et al., 2010). In logically relevant (Anobile et al., 2006). Currently, very little is
addition, alternative splicing allows the meq gene to form another known about the function of Meq/vIL8 in MDV pathogenesis;
transcript with vIL8 gene, named Meq/vIL8 (Fig. 12.2), which however, since Meq and Meq/vIL8 share the amino-terminal
contains the C-terminal DNA binding region of Meq and exon region, it can be hypothesized that they may regulate MDV lytic,
II/exon III of vIL8. This Meq/vIL8 variant will be discussed in latency, or transformation pathways by competitive mechanisms.
detail in following sections.