A multiple functional protein: the herpes simplex virus type 1 tegument protein VP22
ABSTRACT The herpes simplex virus type 1 (HSV-1) VP22, is one of the most abundant HSV-1 tegument proteins with an average stoichiometry
of 2 400 copies per virion and conserved among alphaherpesvirinae. Many functions are attributed to VP22, including nuclear localization, chromatin binding, microtubule binding, induction
of microtubule reorganization, intercellular transport, interaction with cellular proteins, such as template activating factor
I (TAF-I) and nonmuscle myosin II A (NMIIA), and viral proteins including tegument protein VP16, pUS9 and pUL46, glycoprotein
E (gE) and gD. Recently, many novel functions performed by the HSV-1 VP22 protein have been shown, including promotion of
protein synthesis at late times in infection, accumulation of a subset of viral mRNAs at early times in infection and possible
transcriptional regulation function.
- SourceAvailable from: ncbi.nlm.nih.gov
Article: Herpesvirus assembly and egress.[show abstract] [hide abstract]
ABSTRACT: Herpesvirus particles consist of four morphologically distinct structures, the core, capsid, tegument, and envelope. The inner nucleoprotein core comprising the linear double-stranded DNA genome is included in an icosahedral (T16) capsid shell of 150 hexons and 12 pentons. The capsid is surrounded by a layer of proteinaceous material designated the tegument which, in turn, is enclosed in an envelope of host cell-derived lipids containing virus-encoded (glyco)proteins. Whereas cap- sid formation in the nuclei of infected cells is understood in some detail, the mechanisms of tegumentation and envelop- ment and the intracellular compartments involved have long been disputed. This review focuses on recent findings that demonstrate a rather complex process of herpesvirus matura- tion including primary envelopment of capsids by budding at the inner leaflet of the nuclear membrane and translocation of capsids into the cytoplasm after loss of the primary envelope by fusion with the outer leaflet of the nuclear membrane. Subse- quently, final tegumentation occurs in the cytoplasm and tegu- mented capsids obtain their final envelope by budding into vesicles of the trans-Golgi network. Tegumentation and envel- opment are driven by specific protein-protein interactions that appear, at least in cultured cells, to exhibit a remarkable re- dundancy.Journal of Virology 03/2002; 76(4):1537-47. · 5.08 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The herpes simplex virus 1 (HSV-1) tegument protein VP22 has been utilised as a vehicle for trafficking proteins. It has a remarkable property of exiting the cell that is producing it and entering the neighbouring cells, which has been used to deliver therapeutic proteins, p53 and herpes simplex virus thymidine kinase (tk). It has a complex pattern of expression and subcellular localisation. Functions of VP22 include intercellular transport, binding to and bundling of microfilaments, inducing cytoskeleton collapse, nuclear translocation during mitosis, and binding to chromatin and nuclear membrane. The regions of VP22 which contain each of these functions have not been characterised. Finding the region carrying the property of intercellular spread would facilitate enhancement of transport function. By constructing a series of deletion constructs of VP22 tagged by the green fluorescent protein (GFP) we have mapped the functions of VP22 to specific regions in the polypeptide as follows: intercellular transport - aa 81-195; binding and reorganisation of cytoskeleton - aa 159-267; nuclear targeting, inhibition of cytoskeleton collapse - aa 81-121; and nuclear targeting and facilitation of intercellular transport - aa 267-301. Separation of VP22 functions enables focus on the mechanism of VP22-mediated transport and improve the transportation efficiency of VP22.Gene Therapy 08/2001; 8(14):1051-6. · 4.32 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: We show that the HSV-1 structural protein VP22 has the remarkable property of intercellular transport, which is so efficient that following expression in a subpopulation the protein spreads to every cell in a monolayer, where it concentrates in the nucleus and binds chromatin. VP22 movement was observed both after delivery of DNA by transfection or microinjection and during virus infection. Moreover, we demonstrate that VP22 trafficking occurs via a nonclassical Golgi-independent mechanism. Sensitivity to cytochalasin D treatment suggests that VP22 utilizes a novel trafficking pathway that involves the actin cytoskeleton. In addition, we demonstrate intercellular transport of a VP22 fusion protein after endogenous synthesis or exogenous application, indicating that VP22 may have potential in the field of protein delivery.Cell 02/1997; 88(2):223-33. · 31.96 Impact Factor
VIROLOGICA SINICA, June 2009, 24 (3):153-161
CLC number: R373 Document code: A Article ID: 1674-0769 (2009) 03-0153-09
A Multiple Functional Protein: the Herpes Simplex Virus Type 1
Tegument Protein VP22*
Mei-li LI#, Hong GUO#, Qiong DING and Chun-fu ZHENG**
(State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071,
Abstract: The herpes simplex virus type 1 (HSV-1) VP22, is one of the most abundant HSV-1 tegument proteins
with an average stoichiometry of 2 400 copies per virion and conserved among alphaherpesvirinae. Many
functions are attributed to VP22, including nuclear localization, chromatin binding, microtubule binding,
induction of microtubule reorganization, intercellular transport, interaction with cellular proteins, such as template
activating factor I (TAF-I) and nonmuscle myosin II A (NMIIA), and viral proteins including tegument protein
VP16, pUS9 and pUL46, glycoprotein E (gE) and gD. Recently, many novel functions performed by the HSV-1
VP22 protein have been shown, including promotion of protein synthesis at late times in infection, accumulation
of a subset of viral mRNAs at early times in infection and possible transcriptional regulation function.
Key words: Herpes simplex virus type 1 (HSV-1); VP22; Intercellular trafficking; Protein interaction; Tegument
Human herpes simplex virus type 1 (HSV-1), a
nuclear replicating DNA virus, is a widespread human
pathogen that causes a lytic infection in the mucosal
epithelial cells and a life-long latent infection in
neurons. HSV-1 has a distinctive feature of having
more than 20 tegument proteins between its capsid
shell and envelope (29). Tegument proteins have been
shown to play a variety of roles in infection including
the regulation of viral and host gene expression and
the promotion of virus assembly and egress. An
essential tegument protein, VP22, the product of the
UL49 gene of HSV-1, has received notable attention
for its large number of molecules in each polypeptide
per virion (2400 molecules/virion) (18). It is a highly
basic, rich in proline residues, nuclear phosphoprotein
(14, 16, 19), capable of forming higher-order structures
consisting of dimers or tetramers (33). VP22 contains
301 amino acids and has a predicted molecular weight
of 32 kDa (16). It is conserved within the alpha-
herpesvirus family, and undergoes a number of post-
translational modifications during infection, including
nucleotidylation, ADP-ribosylation and phosphory-
lation by at least two cellular kinases, casein kinase II
Received: 2009-02-19, Accepted: 2009-04-08
* Foundation items: The Startup Fund of the Hundred Talents
Program of the Chinese Academy of Science (20071010-
141); National Natural Science Foundation of China
(30870120); Open Research Fund Program of the State
Key Laboratory of Virology of China (2007003,
# Equal contribution author.
** Corresponding author.
Phone: +86-27-87198676, E-mail: email@example.com.
154 Virol. Sin. (2009) 24: 153-161
and protein kinase C (PKC), and one virion protein
kinase UL13 (36).
A number of functions have been attributed to VP22
and these functions are determined by different
regions of this protein (1). VP22 possesses at least two
separate determinants of nuclear and nucleolar
localization (1, 21) and the protein accumulates to
high levels in the nuclei of either infected cells (36) or
stable VP22 expression cell lines (37). In cells, VP22
is first localized in the cytoplasm, where it binds to
microtubules and induces collapse of the cytoskeleton,
creating a large perinuclear lump. After the nuclear
membrane has disintegrated in early mitosis, VP22
translocates into the nucleus and binds to chromatin,
where it remains until after completion of mitosis and
during the next interphase (1, 28). A recent study
showed that nuclear VP22 targeted unique subnuclear
structures early (<6 hpi) during HSV-1 infection and
reduced the number of non-ring nucleolin patterns that
seemed to imply that VP22 might function to inhibit
nucleolar disassembly, thus stabilizing these structures
(26). A mutant HSV lacking VP22 was able to
assemble enveloped virions that reached extracellular
compartments. This mutant produced virions with
reduced immediate-early proteins (ICP0 and ICP4)
and displayed delayed viral protein synthesis (15).
Another VP22 null mutant described recently displayed
defects in reaching extracellular compartments and in
cell-to-cell spread (8). These two VP22 null viruses
also decreased packaging of both glycoproteins gD
and gE (8, 15). Recently, it was reported that the
expressions of ICP0, gD and gE were regulated by the
level of phosphate presented on VP22 (39). VP22
interacts with tegument protein VP16, α-trans-in-
ducing factor (α-TIF), and relocates it to a novel
macromolecular assembly in coexpressing cells (13).
Thus, VP22 plays some role in the final assembly of
HSV, although likely in a redundant fashion with
other tegument proteins (37). VP22 also can incor-
porate the mRNA into the virion and transport the
mRNA to uninfected cells (43). Another important
role of VP22 is that it can interact with template
activating factor I (TAF-I) and impair the nucleosome
assembly on entering viral DNAs (50).
Moreover, VP22 has the capability to spread
intercellularly to adjacent cells after infection or trans-
fection solely with a plasmid encoding VP22 (8, 9).
This property is maintained in proteins fused with
VP22, which can be used to transfer potentially
therapeutic proteins into target cells. Furthermore,
recent reports showed that VP22 was involved in
promotion of protein synthesis, accumulation of a
subset of viral mRNAs (7), and in transcriptional
regulation (55). All of those studies imply that VP22
is important to virus replication. However, the detailed
roles of VP22 during HSV-1 infection remain unclear.
Some of its functions are described below.
VP22 is an efficient intercellular transporter, able to
transfer into neighboring cells and translocate to the
nucleus of the target cell (9). After expression in
transfection cells, VP22 protein is exported from
transfected cells via a non-classical Golgi-independent
pathway. After secretion, VP22 can be efficiently
internalized into the neighboring non-transfected cells
by a poorly understood mechanism. Indeed, VP22 has
been used as a cell-penetrating peptide/protein (CPP)
(42). Many experiments have demonstrated that VP22
could enhance intercellular trafficking of proteins
Virol. Sin. (2009) 24: 153-161 155
fused to its N-or C-terminus in vitro and in vivo (17,
52, 53), and trafficking of VP22 was not restricted to
particular tissues and species (17, 52). Moreover,
VP22-fusion proteins retained both VP22-mediated
transport properties and the biophysiological functions
of the linked passenger proteins, enhancing the
therapeutic effects of transduced genes and proteins.
This property has been observed with VP22-linked
p27, p53, CD (cytosine deaminase), SuperCD, which
is the fusion protein of yeast CD with yeast uracil-
phosphoribosyltransferase, and human papillomavirus
E2 for delivery to tumors (24, 25). The property was
also found in the fusion protein of VP22 with green
fluorescent protein (VP22-GFP) following adenovirus-
mediated transgene delivery to the central nervous
system (CNS) neurons and others have also reported
that VP22-GFP has the property of intercellular
trafficking (9, 11, 25). Furthermore, VP22 mediated
intercellular trafficking of IkappaB-alpha can efficiently
inhibit both constitutive and inducible nuclear factor
kappa B (NF-kappaB) activation (47). VP22-mediated
intercellular protein delivery is also useful in en-
hancing the efficacy of myocardial gene therapy (3, 4,
53) and the effects of gene delivery for somatic gene
therapy of Duchenne muscular dystrophy (DMD) (53,
54). The fusion gene of VP22–β-galactosidase (βGal)
transfection resulted in higher amounts of protein
expression compared with βGal transfection, and this
study showed that VP22 had a remarkable secretory
ability in living cells (32). Preclinical evaluation using
the thymidine kinase (TK)-VP22 fusion protein
revealed an enhanced cytotoxicity in vitro and in vivo
using mixed populations of wildtype and expressing
cells (53). However, some authors reported that fusion
of HSV TK to VP22 did not result in intercellular
trafficking of the protein (2). In fact, others could not
detect VP22-GFP trafficking in living cells, only in
fixed cells. So it was hypothesized that this difference
resulted from a concentration effect or removal of in-
terfering components (11, 17), and it was even sug-
gested that VP22 nuclear homing in living cells was
an experimental artifact (27). Therefore, existing
studies of VP22 intercellular spread remain confusing
and difficult to interpret, but it should be pointed out
that some proteins are readily extracted during
methanol fixation of cells and that covalently bound
polypeptides of a size nearly equivalent to or larger
than VP22 could be expected to change the properties
of the protein (44). However, Rutjes pointed out that
VP22 could have a negative effect on the solubility of
some fusion proteins, which consequently precluded
intercellular trafficking (40).
Although it was reported that amplification of the
immune response might occur via mechanisms other
than VP22-mediated intercellular spread of antigen
(35), VP22 could nevertheless be used to augment the
potency of DNA vaccines (20, 38, 41). Moreover, it
has been shown that VP22 could transport the mRNA
to uninfected cells (43). All of these findings suggest
that the VP22-mediated protein delivery system can
be a useful and potential tool to enhance the efficacy
of gene therapy.
PROMOTION OF PROTEIN SYNTHESIS AND
ACCUMULATION OF mRNAs
Previous studies of a UL49 deletion mutant showed
that VP22 greatly enhanced plaque size and viral
replication at low multiplicities of infection (8, 37).
UL49 deletion virions also contained decreased amounts
of ICP0, gE and gD (8, 15). A recent investigation,
156 Virol. Sin. (2009) 24: 153-161
aiming to determine whether the latter phenomenon
was due to decreased virion incorporation or decreased
synthesis of ICP0, gE and gD in the absence of VP22,
showed that VP22 was required for optimal protein
synthesis at late times in infection and the accumu-
lation of at least gE, gD and virion host shutoff (vhs)
mRNAs at early times in infection (7). Interestingly,
VP22 effects on protein synthesis and mRNA levels
are distinct and separable with regards to both timing
during infection and the genes affected (7). VP22 has
also been shown to interact with mRNA and is found
in both the nucleus and cytoplasm pointing to a
possible direct role for VP22 in mRNA export and/or
translation. VP22 interacts with tegument protein
VP16, a component of primary enveloped virions,
which is also a potent transcriptional activator of viral
immediate-early (IE) genes and can recruit various
transcriptional coactivators to target gene promoters
(13). In addition, the VP16/VP22 complex can interact
with the UL41-encoded protein vhs which is a
riboendonuclease that specifically cleaves host and
viral mRNAs (48). So VP22 may promote protein
synthesis and contribute to mRNA accumulation by
enhancing the effect of VP16 or modulating the
RNase activity of vhs. The details of the mechanisms
involved in protein synthesis and accumulation of
mRNAs require further investigation.
POSSIBLE TRANSCRIPTIONAL REGULATION
VP22 interacts with VP16 and enhances the effect
of VP16 (13). VP22 locates to the cell nucleus where
it binds to chromatin (1, 28) and it also specifically
inhibits nucleosome assembly by binding to TAF-1
(50). In addition, VP22 has a special relationship with
the important viral transcriptional regulatory factor
ICP0 (15). Previous studies on VP22 indicated that it
was highly phosphorylated during HSV-1 infection
(36), it is correlated in its function to certain links
during virion assembly (8, 15), and has the capacity to
stabilize the microtubule (10, 21). All these studies
showed that VP22 might have some transcriptional
regulation function. A recent paper demonstrated that
VP22 alone in the cellular environment inhibited
transcriptional activation of different viral trans-
criptional regulatory factors on different viral gene
promoters (55). Perhaps VP22 performs these functions
by interacting with viral or cellular proteins. However
whether VP22 has the same transcriptional regulation
function during virus infection is still unknown.
ITS INTERACTION PROTEINS AND POTENTIAL
The exact roles of VP22 in the virus life cycle remain
poorly understood. However, it is likely that various
dynamic interactions of VP22 with different cellular
proteins and/or viral proteins are required.
VP22 exhibits the properties of a classical microtubule-
associated protein, reorganizing and stabilizing the
host cell microtubule network and hyperacetylating
these stabilized microtubules (MTs) (10, 21). While
the role of the VP22-microtubule interaction during
infection has yet to be determined, it would seem that
phosphorylation may play an important role in
ensuring that this interaction is not dominant over the
other activities of VP22 during infection (39) and
microtubule reorganization may function as a mecha-
nism to regulate VP22 nuclear localization (21).
Microtubule reorganization is important for viral
exocytosis and for transport of HSV-1 capsids to the
Virol. Sin. (2009) 24: 153-161 157
nucleus (17). In addition, VP22 interacts with non-
muscle myosin IIA (NMIIA) (49), a motor protein
which is recruited to the actin cytoskeleton and has
been reported to be involved in numerous dynamic
cellular processes, including Golgi budding, vesicle
secretion, cell spreading, cleavage and migration, and
cell adhesion (45). The VP22-myosin interaction
provides evidence for an interaction with a network of
myosin-actin filaments other than the microtubule/
dynein system. NMIIA may be involved in virus
maturation (49). The interaction between VP22 and
MT/NMIIA could be relevant to assembly and egress,
and could play a role in virus transport. Further work
will be necessary to identify the exact role of the
A previous study showed that VP22 interacted with
a cellular histone chaperone TAF-I (50), which has
been shown to promote more ordered transfer of
histones to naked DNA through a direct interaction
with histones (31). TAF-I, as a subunit of the INHAT
(inhibitor of acetyltransferases) protein complex, also
binds to histones and masks them from acting as
substrates for the acetyltransferases p300 and PCAF
(46). The study further showed that interaction with
VP22 inhibited the activity of TAF-Iα in chromatin
assembly, while, conversely, overexpression of TAF-
Iα suppressed HSV infection in vivo. VP22-binding
proteins may form an INHAT complex pp32/PHAPI
that could be relevant to HSV DNA organization early
in infection (50). But other functions such as trans-
criptional regulation cannot be excluded and further
work is necessary to prove this interaction physiologi-
VP22 interacts with membranes and is also believed
to possess the ability to multimerize, and more
specifically with membranes of the acidic compart-
ments of cells that may include the trans-Golgi network
(TGN) (6, 33). A previous study of VP22, which used
live-cell fluorescence during virus infection, demon-
strated a punctate cytoplasmic localization reminiscent
of the Golgi apparatus (12). Current evidence supports
a model that final tegumentation and envelopment of
herpesviruses occur when nucleocapsids bud into
cytoplasmic vesicles, which may be derived from the
TGN (6). Consistent with this observation, VP22 is
packaged into virions during final envelopment as
nucleocapsids bud into TGN-derived vesicles (30).
VP22 can interact with the cytoplasmic tails of gD and
gE, and may facilitate the interaction of viral nucleo-
capsids with glycoproteins lining up on the mem-
branes of TGN-derived vesicles, perhaps also through
its interaction with VP16 (62). The interaction
between VP22 and VP16, gD or gE/gI may promote
A novel interaction between VP22 and the US9
protein (pUS9) has been screened by yeast two-hybrid
recently (23). pUS9 of HSV-1 is a tegument protein
and the US9 gene is highly conserved among the
members of the alpha subfamily of herpesviruses (5).
More recent studies indicated that pUS9 is associated
with the endoplasmic reticulum and Golgi apparatus,
as well as with cytoplasmic, unenveloped capsids. On
the other hand, a detailed study of the pseudorabies
virus (PRV) demonstrated that pUS9 of PRV was a
type II membrane protein associated with Golgi or
perinuclear membranes (22). Although the US9 gene
is dispensable for viral replication in cultured cells, it
is believed that pUS9 is a lysineless ubiquitinated
protein that interacts with the ubiquitin dependent
pathway for degradation of proteins. This function
158 Virol. Sin. (2009) 24: 153-161
may be initiated at the time of entry of the virus into
the cell (5). A recent observation showed that pUS9
was necessary for long distance anterograde axonal
transport of viral nucleocapsids (22). It could represent
an additional viral mechanism to regulate specific
cellular and virus functions. This interaction is likely
to be involved in the process of secondary envelop-
ment during viral assembly. However, whether this is
a structural or regulatory interaction requires further
pUL46 (VP11/12) is another novel protein which
interacts with VP22 (23), it is an abundant virion
tegument phosphoprotein with approximately 1200
molecules per virion (18). pUL46 and VP22 have
similar localization and both are membrane-associated
proteins, however, pUL46 binds the membrane less
strongly than VP22 (34). It has been reported that the
HSV-1 DNA fragment containing the UL46 gene
enhanced the efficiency of VP16-mediated gene
expression (56). Also pertinent to this report is the
observation that VP22 interacts with VP16 (13); it
was reported that pUL46 could also interact with
VP16 (51). The interactions among these three tegument
proteins indicate that they may simultaneously play
some role in the replication of the virus. It seems that
pUL46 is an inner layer of the tegument protein which
associates directly with capsids, while VP16 and
VP22 belong to the peripheral layer composed of
proteins that interact with the envelope. The
mechanism of interaction between VP22 and pUL46
still needs further study.
Herpesviruses are highly disseminated in nature.
HSV-1 is one of the most intensively investigated
herpesviruses which serves as a model and a tool for a
wide range of applications including the study of
translocation of proteins, membrane structure, gene
regulation, gene therapy and cancer therapy. VP22,
the essential tegument protein of HSV-1, is conserved
within the alpha-herpesvirus family, and has multiple
functions in virus replication and spread.
VP22 has intercellular trafficking properties. It is
necessary for localization of ICP0 to putative sites of
viral assembly within the cytoplasm and can also
package RNA into the virion. Recently, many novel
functions attributed to the HSV-1 VP22 protein were
shown, including promotion of protein synthesis at
late times in infection, accumulation of a subset of
viral mRNAs at early times in infection and a possible
transcriptional inhibition function in some genes
VP22 can accumulate in the nucleus as well as
exploit the host cytoskeleton suggesting that this
unusual tegument protein may have an important role
in herpesvirus infection, replication and pathogenesis.
Although the exact molecular mechanisms are still not
clearly understood, exploring the mechanism of how
VP22 is imported to the nucleus may advance the
knowledge of the pathogenesis of the herpesviruses
and enable the development of new antiviral approaches.
VP22 can interact with at least five virus proteins
(VP16, gE, gD, pUS9 and pUL46) and at least three
cellular proteins (TAF-I, NMIIA and MT), and plays
different roles according to these different interactions.
From these reports we can conclude that the in-
teractions of VP22 with different cellular proteins and/
or virus proteins are important for its functionality. So
it is necessary to establish the network of protein
(VP22)-protein (host/virus) interactions that facilitate
Virol. Sin. (2009) 24: 153-161 159
further definition of the potential roles and possible
mechanism of VP22. Understanding the mechanism of
the multifunctional regulatory protein VP22 may
advance our knowledge of the HSV-1 and promote the
exploitation of efficient methods for preventing viral
infection and antiviral therapy.
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