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virion begins at the cell surface as a result of interactions between mediated by ORF22 protein. Cell cycle progression is an impor-
the penton base with the cell surface integrins. Such interactions tant step to stimulate the expression of cellular genes involved in
result in detachment of fibres from the virion on the cell surface synthesis of precursor dNTPs and RNA processing proteins –
(Nakano et al., 2000). After endocytosis, the clathrin-coated required for viral DNA and mRNA synthesis, respectively – and
vesicles containing fibreless virions mature into endosomes. activation of signalling pathways required for protein synthesis
Acidification takes place during endosomal maturation resulting (Berk, 2013). Mastadenovirus E1A proteins and FAdV-1 Gam-1
in the release of penton base, peripentoneal hexon trimers and the and ORF22 protein physically bind pRB, a tumour suppressor
internal capsid proteins such as IIIa, VI and VIII, and activation of gene, to stimulate cell cycle progression through E2F-dependent
the viral protease, which is also essential for virus assembly (Berk, transcription (Lehrmann and Cotten, 1999; Berk, 2013). E1A
2013). Lysis of the endosome for the release of the partially dis- proteins form a trimeric complex with pRB and p300 or CBP,
assembled virion into the cytosol is mediated by the membrane which are nuclear lysine acetyl transferases (Ferreon et al., 2009).
lytic domain of protein VI (Wiethoff et al., 2005). The subvirion FAdV-1 Gam-1 also binds pRB and seems to form complexes
particles in the cytosol are transported to the nucleus via dynein with p120 E4F and histone deacetylase 1 (HDAC1) rendering
along microtubules towards the perinuclear region (Leopold et HDAC1 inactive. Inhibition of HDAC1 sumoylation is another
al., 2000). Subviral particles then bind to nuclear pore complexes mechanism by which Gam-1 inactivates HDAC1 (Colombo et al.,
(NPCs) for final capsid disassembly and release of the viral DNA 2002). Gam-1 also disrupts the promyelocytic leukaemia (PML)
into the nucleus (Berk, 2013). nuclear bodies by inhibition of PML sumoylation (Colombo et
al., 2002). PML is known to play antiviral functions for both RNA
Biosynthesis and DNA viruses (Everett and Chelbi-Alix, 2007).
Viral gene transcription occurs in both DNA strands and is mostly Virus infections often stimulate the expression of pro-
known in HAdV-2 and HAdV-5. Viral DNA associated with the apoptotic genes including the tumour suppressor gene p53.
VII protein is released to the nucleus from the subviral particle Induction of p53 by mastadenoviruses is mediated by E1A
docking on the nuclear pore (Xue et al., 2005). The association of proteins as a consequence of abnormal induction of cell cycle
the viral DNA with the VII protein prevents the cellular dsDNA progression (Berk, 2013). Similar mechanisms that stimulate
break response from the host cell (Karen and Hearing, 2011). the expression of p53 may also occur in avian adenoviruses.
Subsequent steps involve the partial replacement of protein VII Adenoviruses have evolved mechanisms to counteract the nega-
by acetylated nucleosomes from the host (Berk, 2013). tive effects of p53 on the viral replication cycle. Mastadenovirus
Viral genes are transcribed early (E) and late (L) in infec- E4ORF6 in association with E1B 55 K forms complexes with
tion, though E genes continue to be expressed at late times and Cullin (Cul)-based E3 ubiquitin ligase to promote p53 degra-
the L promoter can lead to transcription at low levels early in dation via the proteasome (Querido et al., 2004). Formation
infection. Detailed transcriptional maps of avian adenoviruses of such ligase complexes is mediated by BC-box motifs (BC2
are determined in only FAdV-1 and 9 (Payet et al., 1998; Ojkic and BC3) present in E4ORF6, which are preceded by Cul
et al., 2002), whilst partially predicted transcriptional maps are boxes (Cul 2 and 5) and XCXC motif (Gilson et al., 2016).
reported for other aviadenoviruses (Griffin and Nagy, 2011; E4ORF6-like genes have been identified in some atadenoviruses
Kaján et al., 2012; Marek et al., 2013, 2014a,b, 2016). In general, such as DAdV-1 E4 gene and aviadenoviruses – homologues to
transcription of E genes takes place before the onset of DNA ORFs 24, 14A and 14 of FAdVs, TAdV (serotypes 1, 4 and 5),
replication, while transcription of L genes significantly increases PiAdV-1 and DAdV-2ORFs (Corredor et al., 2006; Gilson et
after DNA replication (Berk, 2013). E genes are involved in host– al., 2016). DAdV-1 E4 contains the Cul2 and BC3 boxes and
virus interactions including cell cycle progression, counteraction has been shown experimentally to bind Cul 2 and 5 to form
of the host antiviral and immune response defences, regulation these ligase complexes. Aviadenovirus ORFs 24, 14A and 14
of apoptosis, viral DNA replication (E2 genes) and activation of lack Cul2 box but contains the XCXC motif and BC3 box. BC3
the late promoter for L gene expression. E gene function has been box is missing in FAdV-4 ORF14A, FAdV-2 ORF14 and FAdV-9
mostly studied in mastadenoviruses, whilst the function of only ORF14 (Fig. 10.2) (Corredor et al., 2006; Gilson et al., 2016).
a few genes have been determined: ORFs 8 (Gallus anti morte, ORFs 24 and 14 together with ORFs 2, 13 and 12 have been
Gam-1) and 22 of FAdV-1 (CELO virus) and ORF1 of FAdV-9 also grouped within the superfamily III helicases and related to
(Lehrmann and Cotten, 1999; Deng et al., 2016). the NS-1 proteins (Washietl and Eisenhaber, 2003). However,
In mastadenoviruses, E1A genes are the first transcribed to the lack of amino acid identities between ORFs 24 and 14
stimulate cell cycle progression as well as the transcription of the and NS-1 proteins (Corredor et al., 2006) and the presence of
E1B, E2, E3 and E4 genes. FAdV-1 Gam-1 and ORF22 and atad- XCXC and BC-box motifs further suggest their classification as
enovirus E 43 (ovine adenovirus 7) are functionally equivalent E4ORF6-like genes. Therefore, aviadenovirus ORFs 24 and 14
to E1A genes (Lehrmann and Cotten, 1999; Kümin et al., 2004; are predicted to form E3 ligase complexes to target cellular pro-
Harrach et al., 2011) and probably expressed soon after infection. teins, probably including p53. As mentioned previously, FAdV-1
ORF22 is present in all sequenced aviadenoviruses up to date, Gam-1 disrupts PML (Colombo et al., 2002), whose antiviral
whereas Gam-1 is absent in DAdV-2 and GoAdV-4 (Table 10.2). function is known to be p53-independent or dependent (Everett
Therefore, these observations suggest alternative mechanisms and Chelbi-Alix, 2007). Therefore, Gam-1 also seems to have
for induction of cell cycle progression by these viruses, probably indirect functions on counteracting p53-mediated apoptosis.