Download Manipulation of the host translation initiation complex eIF4F by DNA

Post-Transcriptional Control: mRNA Translation, Localization and Turnover
Manipulation of the host translation initiation
complex eIF4F by DNA viruses
Derek Walsh1
National Institute for Cellular Biotechnology, Dublin City University, Dublin 9, Ireland
Abstract
In the absence of their own translational machinery, all viruses must gain access to host cell ribosomes
to synthesize viral proteins and replicate. Ribosome recruitment and scanning of capped host mRNAs is
facilitated by the multisubunit eIF (eukaryotic initiation factor) 4F, which consists of a cap-binding protein,
eIF4E and an RNA helicase, eIF4A, assembled on a large scaffolding protein, eIF4G. Although inactivated
by many viruses to inhibit host translation, a growing number of DNA viruses are being found to employ
diverse strategies to stimulate eIF4F activity in infected cells and maximize viral protein synthesis. These
strategies include stimulation of cellular mTOR (mammalian target of rapamycin) signalling to inactivate
4E-BPs (eIF4E-binding proteins), a family of translational repressors that limit eIF4E availability and eIF4F
complex formation, together with modulating the activity of the eIF4E kinase Mnk (mitogen-activated
protein kinase signal-integrating kinase) in a variety of manners to regulate both host and viral mRNA
translation. In some cases, specific viral proteins that mediate these signalling events have been identified,
whereas others have been shown to interact with host translation initiation factors or complexes and modify
their activity and/or subcellular localization. The present review outlines current understanding of the role
of eIF4F in the life cycle of various DNA viruses and discusses its potential as a therapeutic target to suppress
viral infection.
The eIF (eukaryotic translation initiation
factor) 4F complex and translation
initiation
Eukaryotic mRNAs are capped at their 5 -end by a 7-methylGTP and polyadenylated at their 3 -end, both of which
function during translation initiation. Ribosome recruitment
to the 5 -end is facilitated by eIF4F, which consists of a
small cap-binding protein, eIF4E, an ATP-dependent RNA
helicase, eIF4A, and a large scaffold protein, eIF4G (Figure 1)
[1]. eIF4G also binds PABP [poly(A)-binding protein],
an interaction that mediates 5 →3 -end communication
thought to act as a quality-control mechanism to promote
efficient translation of intact correctly processed mRNAs.
In addition, eIF4G interacts with the multisubunit complex
eIF3, bridging the small (40S) ribosomal subunit to the eIF4F
complex. Once assembled on the cap, the helicase activity
of the eIF4F complex unwinds secondary structure in
the 5 -UTR (untranslated region) to facilitate ribosomal
Key words: eukaryotic translation initiation factor 4F (eIF4F), mammalian target of rapamycin
(mTOR), mitogen-activated protein kinase signal-integrating kinase (Mnk), translation initiation,
viral infection.
Abbreviations used: ASFV, African swine fever virus; dsDNA, double-stranded DNA; E4-ORF,
E4 region containing open reading frame; eIF, eukaryotic translation initiation factor; 4E-BP,
eIF4E-binding protein; EBV, Epstein–Barr virus; ERK, extracellular-signal-regulated kinase; HCMV,
human cytomegalovirus; HPV, human papillomavirus; HSV-1, herpes simplex virus type 1; ICP,
infected cell protein; IRES, internal ribosome entry site; KSHV, Kaposi’s sarcoma-associated
herpesvirus; MAPK, mitogen-activated protein kinase; Mnk, MAPK signal-integrating kinase;
mTOR, mammalian target of rapamycin; mTORC, mTOR complex; PABP, poly(A)-binding protein;
PI3K, phosphoinositide 3-kinase; PIC, pre-initiation complex; PP2A, protein phosphatase 2A;
siRNA, short interfering RNA; SV40, simian virus 40; TSC, tuberous sclerosis complex; UTR,
untranslated region; VACV, vaccinia virus; VARV, variola virus; VHS, virion host shut-off.
1
email [email protected]
Biochem. Soc. Trans. (2010) 38, 1511–1516; doi:10.1042/BST0381511
scanning, a process whereby the 40 S ribosome-containing
PIC (pre-initiation complex) moves along the 5 -UTR until
it encounters a start codon. At this point the PIC is joined
by the large (60S) ribosomal subunit and translation of the
mRNA commences [1].
The availability of the cap-binding subunit of eIF4F
is regulated by a family of small 4E-BPs (eIF4E-binding
proteins) [1]. In their hypophosphorylated state, 4E-BPs
bind to the same site on eIF4E as eIF4G, thereby acting
as competitive inhibitors of eIF4F complex formation
(Figure 1). In response to a variety of environmental cues
to stimulate translation, signalling through pathways such
as PI3K (phosphoinositide 3-kinase)–Akt–TSC (tuberous
sclerosis complex)/PRAS40 (proline-rich Akt substrate of
40 kDa) mediates activation of mTOR (mammalian target
of rapamycin), a kinase that phosphorylates both eIF4G
and 4E-BP. Phosphorylation of 4E-BP occurs on multiple
sites and causes it to release eIF4E, making the cap-binding
subunit available for eIF4F complex formation. Once present
in an eIF4F complex, eIF4E is phosphorylated by the
eIF4G-associated Mnk [MAPK (mitogen-activated protein
kinase) signal-integrating kinase], which acts as a convergence
point for two important mitogenic signalling pathways,
ERK (extracellular-signal-regulated kinase) and p38 MAPK.
However, the exact function of eIF4E phosphorylation
remains unclear, correlating both positively and negatively
with translation rates under different circumstances.
Mammalian viruses have evolved an array of strategies
that target eIF4F to influence both viral and host mRNA
translation. Many RNA viruses inactivate eIF4F to inhibit
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Figure 1 The eIF4F complex and cap-dependent translation
Figure 2 DNA virus proteins that influence eIF4F activity
initiation
Key factors in eIF4F-mediated ribosome recruitment are coloured. eIF4G
Details of individual proteins are provided in the main text. Proteins from
the same virus are the same colour: HSV-1 (green), adenovirus (Ad;
(red) acts as a scaffold for the assembly of eIF4F by binding the
cap-binding protein, eIF4E (green) and the helicase eIF4A (turquoise).
eIF4G also binds PABP (brown), which circularizes mRNAs, Mnk (purple),
red), KSHV (purple), HCMV (turquoise) and SV40 (blue). T-bars represent
inhibition. Lines with circular endings represent interactions between
viral proteins and host factors. Notably, it remains to be determined in
which phosphorylates eIF4E, as well as eIF3 (blue), which bridges the
small 40 S ribosomal subunit to eIF4G. mTOR mediates eIF4G and 4E-BP
phosphorylation, whereas ERK and p38 MAPK activate Mnk. Circled P’s
some cases whether these interactions are direct or indirect. Circled P’s
represent phosphorylation events.
represent phosphorylation events.
host protein synthesis, initiating translation of their own
mRNAs by cap-independent processes that include the
use of IRESs (internal ribosome entry sites) [2]. However,
the variety of both inhibitory and stimulatory approaches
employed by DNA viruses to manipulate eIF4F and the viral
factors involved (outlined in Figure 2) are just beginning to
emerge.
mRNAs under these conditions is mediated by a common
200 nt sequence in their 5 -UTR, termed the tripartite leader,
which complements 18 S rRNA and binds eIF4G-associated
100 k, promoting initiation by a ribosome translocation
process called ‘shunting’, which is distinct from conventional
scanning [10–15].
Papillomaviruses and polyomaviruses
Adenoviruses
Adenoviruses were named after the adenoid tissue in which
they were first discovered and cause acute respiratory
infections, as well as conjunctivitis and infantile gastroenteritis. Their non-enveloped virions contain a linear 26–
45 kb dsDNA (double-stranded DNA) genome that is
replicated in the nucleus, whereas transcripts are capped and
polyadenylated.
Early in infection, only low levels of viral proteins are produced, whereas total protein synthesis is increased coincident
with 4E-BP inactivation [3,4]. 4E-BP1 phosphorylation has
been shown to involve adenovirus E4-ORF (E4 region
containing open reading frame) 1-mediated activation of
PI3K and PP2A (protein phosphatase 2A)-dependent E4ORF4-mediated activation of mTOR [5]. At later stages
of infection, host translation is inhibited, despite continued
phosphorylation of 4E-BPs. This inhibition correlates with
desphosphorylation of eIF4E [6,7], which is caused by
the displacement of Mnk from the eIF4F complex by the
binding of adenovirus 100 k protein to the C-terminus of
eIF4G [8,9]. In contrast, selective translation of late viral
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Authors Journal compilation These small non-enveloped viruses contain a circular 5–
8 kb dsDNA genome and are associated with a variety
of cancers. HPVs (human papillomaviruses) induce benign
lesions such as warts as well as uterine and urogenital
malignancies. Although little is known about their effects
on eIF4F, there is evidence that HPV deregulates 4EBP1, which may contribute to cellular transformation [16].
Notably, polycistronic HPV mRNAs utilize both scanning
and shunting mechanisms to translate distinct reading frames
[17].
Deriving their name from the Greek for ‘multiple tumour
virus’, polyomaviruses include SV40 (simian virus 40), BK
virus and JC virus. Early in SV40 infection, host translation
is unaffected and the mTOR substrates 4E-BP1 and eIF4G
are phosphorylated. As infection progresses, however, the
accumulation of small T-antigen causes a PP2A-dependent
dephosphorylation of 4E-BP1, leading to disruption of eIF4F
and attenuation of host protein synthesis [18]. The possibility
that late SV40 mRNAs employ cap-independent mechanisms
of translation under such conditions is supported by the
demonstration of IRES activity in SV40 polycistronic 19 S
late mRNAs [19].
Post-Transcriptional Control: mRNA Translation, Localization and Turnover
Herpesviruses
Herpesviruses are widely disseminated in nature, eight
of which infect humans. They exist in both productive
(lytic) and non-productive (latent) states, allowing them
to establish lifelong infections of their host. Herpesviruses
are enveloped and have a linear 124–230 kb dsDNA
genome that is replicated in the nucleus, whereas their
mRNAs are capped and polyadenylated. They are broadly
divided into three subfamilies, the α-, β- and γ -herpesviruses.
HSV-1 (herpes simplex virus type 1)
HSV-1 is an α-herpesvirus that causes cold sores, corneal
blindness and encephalitis. The replicative cycle is short
and causes a robust inhibition of host protein synthesis
mediated by the suppression of host transcription and mRNA
processing/export, as well as the activity of VHS (virion host
shut-off), a viral endonuclease that associates with eIF4A and
eIF4H [20]. In addition to degrading host mRNAs, VHS is
thought to play a role in regulating the temporal pattern of
viral mRNA expression.
Until recently, whether inactivation of eIF4F also
contributes to host shut-off during HSV-1 infection remained
unknown. When examined, however, HSV-1 was found
to stimulate eIF4E phosphorylation and eIF4F complex
formation in resting primary human cells [21]. eIF4E
phosphorylation is mediated by p38 MAPK activation [21],
which is induced by the HSV-1 protein ICP (infected cell
protein) 27 [22,23], whereas ERK is inactivated. Inhibitors
of p38 MAPK or Mnk prevent eIF4E phosphorylation and
reduce both the rates of protein synthesis and the spread
of virus in cultures infected with small amounts of HSV-1,
but have little impact when large input doses of virus are
used [21]. As such, the eIF4E kinase Mnk plays a subtle,
but biologically important, role in stimulating viral protein
synthesis.
HSV-1 infection also activates mTOR signalling, resulting
in phosphorylation and degradation of 4E-BP1 [21]. 4EBP1 degradation is suppressed by the mTOR inhibitor
rapamycin or the proteasome inhibitor MG132, suggesting
that 4E-BP1 is degraded in infected cells by the proteasome
subsequent to its release from eIF4E. Whether specific viral
functions regulate 4E-BP1 phosphorylation and target it for
degradation remains unknown.
The HSV-1 protein ICP6 has been shown to associate
with eIF4G and enhance the eIF4E–eIF4G interaction in
vitro [24]. The N-terminal domain of ICP6 is homologous
with the cellular chaperone Hsp27 (heat-shock protein 27),
which regulates eIF4F levels during stress responses [25].
Viruses lacking ICP6 fail to increase eIF4F levels despite
inactivating 4E-BP1, suggesting that multiple processes are
involved in fostering eIF4F complex formation in infected
cells. In addition, VHS associates with eIF4A/eIF4H and,
despite its endonuclease activity, has been shown to enhance
translation from IRES elements and sequences within HSV-1
5 -UTRs [26].
Despite polyadenylation of their mRNAs and enhanced
eIF4F complex formation, the association of PABP with
eIF4F is not enhanced by HSV-1 in primary cells and is
decreased in HeLa cells [27,28]. Indeed, PABP is redistributed
to the nucleus during infection [28,29], which may play a role
in nuclear processing and/or shuttling of viral mRNAs and
could potentially contribute to shut-off of host translation.
The multifunctional HSV-1 protein ICP27 associates with
PABP [30], although suggestions that this contributes to the
nuclear redistribution of PABP have been disputed [28,29].
However, when tethered to a reporter RNA, ICP27 can
stimulate translation [31]. In infected cells, ICP27 is required
for efficient synthesis of specific subsets of viral proteins
[32,33]. As such, ICP27, in part through its association
with PABP and induction of p38 MAPK, has a complex
multifunctional role in regulating the processing, transport
and translation of viral transcripts.
HCMV (human cytomegalovirus)
HCMV is a β-herpesvirus that causes serious illness in the
immunocompromised and is the leading cause of virusassociated birth defect in newborns. HCMV has a protracted
life cycle and does not dramatically alter host protein
synthesis.
HCMV activates mTOR signalling and phosphorylates
both 4E-BP1 and eIF4G in a manner that is largely insensitive
to rapamycin [27,34]. Infection modifies the substrate
specificities of distinct raptor (regulatory associated protein
of mTOR)- and rictor (rapamycin-insensitive companion of
mTOR)-containing mTORCs (mTOR complexes), termed
mTORC1 and mTORC2 respectively [35]. In addition, the
HCMV protein UL38 associates with TSC2, a component
of the TSC, and prevents it from inhibiting mTORC1 [36].
Torin1, a specific inhibitor of mTORC1 and mTORC2,
blocks 4E-BP phosphorylation and disrupts eIF4F, suppressing virus replication and demonstrating the importance
of rapamycin-insensitive mTOR signalling during HCMV
infection [37].
As HCMV infection progresses, the abundance of core
eIF4F components and PABP is greatly increased, as are
the levels of eIF4F complexes [27]. PAA (phosphonoacetic
acid), which inhibits viral DNA synthesis and progression to
late stages of infection, reduces the accumulation of initiation
factors and levels of eIF4F. As such, increased intracellular
concentrations of initiation factors may play an important
part in driving eIF4F formation during infection. In addition,
HCMV UL69, homologous with HSV-1 ICP27, associates
with eIF4A and PABP and excludes 4E-BP1 from cap
complexes, although the mechanism by which this exclusion
occurs is unknown [38].
By activating p38 MAPK and ERK signalling pathways,
HCMV also stimulates eIF4E phosphorylation [27]. A
combination of p38 MAPK and ERK inhibitors or the
Mnk inhibitor CGP57380 reduces the spread of HCMV
in cultures, demonstrating the importance of Mnk and
eIF4E phosphorylation in the replicative cycle of another
herpesvirus.
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KSHV (Kaposi’s sarcoma-associated herpesvirus)
and EBV (Epstein–Barr virus)
KSHV and EBV are lymphotropic γ -herpesviruses
associated with a variety of disease states, including cancer.
KSHV enhances eIF4F complex formation as well as
p38 MAPK- and ERK-mediated eIF4E phosphorylation
during reactivation from latency in B-cell lines [39]. The
Mnk inhibitor CGP57380 suppresses virus reactivation,
demonstrating that Mnk and eIF4E phosphorylation also
play an important role in the reactivation phase of the
herpesvirus lifecycle. Similar to HSV-1 lytic infection, KSHV
reactivation suppresses host translation, does not stimulate
the recruitment of PABP to eIF4F complexes and results in
a redistribution of PABP to the nucleus [39]. Two KSHV
proteins, K10/10.1 and SOX, have been shown to interact
with PABP, with the latter causing nuclear redistribution
of PABP and inducing cellular mRNA destruction through
aberrant polyadenylation [40,41].
Both KSHV reactivation and EBV infection induce 4EBP1 phosphorylation [39,42]. The vGPCR (viral G-proteincoupled receptor) of KSHV [43] and the latency protein
LMP2A (latent membrane protein 2A) of EBV [42] have been
reported to stimulate mTOR, which may also contribute to
cellular transformation by these viruses.
Poxviruses
Poxviruses are large enveloped viruses that contain a
linear 130–300 kb dsDNA genome. They include VARV
(variola virus), the causative agent of smallpox, and VACV
(vaccinia virus), a poxvirus closely related to VARV that
was used as a vaccine against smallpox. A striking feature
of poxvirus replication is that it occurs exclusively in the
cytoplasm within compartments called viral factories.
Early studies focused largely on the fact that VACV did not
negatively affect eIF4F function, in contrast with many other
viruses being studied at that time [44,45]. Indeed, poxvirus
mRNAs were found to be translated in a cap-dependent
manner albeit with a reduced dependence upon initiation
factors compared with host mRNAs [46–49]. Recent work,
however, has demonstrated that VACV increases eIF4F
complex levels in normal human cells and enhances PABP
binding [50]. Both p38 MAPK and ERK are activated during
infection and stimulate eIF4E phosphorylation. The Mnk
inhibitor CGP57380 suppresses poxvirus replication and
spread during infection with small amounts of virus, an effect
that has been genetically confirmed in Mnk-deficient mouse
embryo fibroblasts [50].
VACV inactivates 4E-BP1, phosphorylating and targeting
it to the proteasome in a rapamycin-sensitive manner similar
to HSV-1 [50]. VACV stimulates mTOR by activating PI3K
signalling, and the PI3K inhibitor LY294002 causes a dramatic
accumulation of hypophosphorylated 4E-BP1, disruption of
eIF4F and a significant decrease in viral protein synthesis
and replication [51]. The fact that rapamycin does not
induce the same effects suggests that rapamycin-insensitive
mTOR, or another LY294002-sensitive function, is the
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Authors Journal compilation dominant regulator of eIF4F formation in VACV-infected
cells.
VACV infection also has a dramatic effect on the
localization of initiation factors within the host cell [50,52].
Specifically, eIF4E and eIF4G are redistributed to discrete
regions within viral factories. Notably, although small
amounts of PABP are also evident within factories, a large
portion of the cellular pool of PABP remains on the periphery
of these structures. The composition of host factors within
viral factories appears to be selective, as the localization of a
number of other RNA-binding proteins remains unaltered.
Whether this is a passive process or mediated by a specific
viral factor(s) remains to be determined.
Asfarvirus
ASFV (African swine fever virus) is the sole member of the Asfarviridae. Similar to poxviruses, ASFV replicates in the cytoplasm of infected cells and has been shown to redistribute
translation initiation factors (eIF4E, eIF4G, eIF2α and
eIF3b), elongation factors (eEF2) and ribosomal P protein
to regions within and around viral replication compartments
[53]. Infection is also accompanied by rapamycin-sensitive
phosphorylation of 4E-BP1, increased levels of eIF4F and
enhanced phosphorylation of eIF4E. Both rapamycin
and the Mnk inhibitor CGP57380 as well as siRNAs (short
interfering RNAs) targeting eIF4E reduce ASFV replication,
underpinning the importance of eIF4F in the ASFV life cycle
[53].
Therapeutic targeting of eIF4F
Suppressing eIF4F activity has gained recognition in the
field of cancer therapeutics because efficient translation
of structurally complex mRNAs encoding growth-related
and anti-apoptotic proteins has a high requirement for
eIF4F, in contrast with the low requirement of structurally
simpler housekeeping mRNAs, offering a potentially safe and
selective means to target tumours. Whereas small DNA viruses (adenovirus/polyomavirus) inactivate eIF4F as infection
progresses, a growing number of larger DNA viruses are
being found to stimulate eIF4F activity. Inhibition of Mnk
suppresses herpesvirus, poxvirus and asfarvirus replication,
albeit modestly [21,27,50,53]. The mTORC1/mTORC2
inhibitor Torin1 disrupts eIF4F and significantly reduces
the replication of representative α-, β- and γ -herpesviruses
[37], whereas siRNAs targeting eIF4F components suppress
asfarvirus and poxvirus protein synthesis [53,54]. Although
not absolutely essential for viral protein synthesis, perhaps
due to residual eIF4F in experimental systems or a low
requirement of viral mRNAs for its activity akin to cellular
housekeeping mRNAs, targeting eIF4F may offer an effective
broad-spectrum approach to suppressing infection by a
number of medically important DNA viruses. In addition,
as a central factor in both DNA virus replication and
cellular transformation, targeting eIF4F might be an effective
approach to treating virus-induced tumours.
Post-Transcriptional Control: mRNA Translation, Localization and Turnover
Funding
D.W. is supported by Science Foundation Ireland [grant numbers
06 IN.1 B80 and 09-RFP-BMT2130] and the Health Research Board
[grant number RP/2007/52].
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Received 27 May 2010
doi:10.1042/BST0381511