Viral modulators of cell death provide new links to old pathways
Pablo M Irusta?, Ying-bei Chenyand J Marie Hardwickz
By observing how viruses facilitate their parasitic relationships
with host cells, we gain insights into key regulatory pathways of
the cell. Not only are mitochondria key players in the regulation
of programmed cell death, but many viral regulators of cell
death also alter mitochondrial functions either directly or
indirectly. Although cytomegalovirus vMIA and Epstein-Barr
virus BHRF1 seem to have opposite effects on mitochondrial
morphology, they both inhibit cell death. Drosophila
Reaper, a regulator of developmental cell death, acts on IAP
(inhibitor of apoptosis) proteins to activate caspases, but
can regulate mitochondrial permeability in vitro. Despite its
pivotal role in Drosophila, homologues of Reaper in other
species were not previously known. Recently, amino acid
sequence similarity was recognized between Drosophila
Reaper and a protein known to be important for the replication
and virulence of mosquito-borne bunyaviruses that cause
human encephalitis. Thus, viral mechanisms for regulating
apoptosis are diverse and not fully elucidated but promise to
provide new insights.
Departments of?zMolecular Microbiology and Immunology, and
yzPharmacology and Molecular Sciences, Johns Hopkins Schools of
Medicine and Public Health, 615 North Wolfe St, Baltimore, Maryland
Current Opinion in Cell Biology 2003, 15:700–705
This review comes from a themed issue on
Cell division, growth and death
Edited by Jonathon Pines and Sally Kornbluth
0955-0674/$ – see front matter
? 2003 Elsevier Ltd. All rights reserved.
adenine nucleotide translocator
inhibitor of apoptosis
non-structural protein encoded on small genome segment
San Angelo bunyavirus
virus mitochondrial inhibitor of apoptosis
Mitochondria, being essential for cell survival, are logical
targets for destruction in a molecular pathway to achieve
cell death. However, it is interesting to note that many
mitochondrial functions and even their genomes can be
discarded under some circumstances . Mitochondria
also contribute to the cell death pathway by serving as
storehouses forpro-death factors that arereleased into the
cytosol . Compelling evidence that mitochondria
actively promote programmed cell death is limited to
mammals and Caenorhabditis elegans, but this concept is
likely to be extended to other species, including unicel-
lular organisms that were not previously thought to
undergo programmed death [2–4]. Cytochrome c, origin-
ally known only for its role in the electron transport chain,
turns out to have a surprising new function once translo-
cated out of mitochondria by an unknown mechanism
after the cell receives a death stimulus. In the cytosol,
cytochrome c becomes a cofactor for caspase-9 activation
by binding to the Apaf-1 protein, facilitating assembly
and activation of the apoptosome and hence promoting
caspase activation and cell death . Thus far, only
mammals seem to utilize cytochrome c in this manner,
but there are other pro-death factors released from mito-
chondria. EndoG and AIF (apoptosis inducing factor) are
both released from mitochondria and translocate to the
nucleus to promote cell death, a strategy apparently
employed bybothmammalsand worms .Themechan-
isms by which these factors pass through the outer mito-
chondrial membrane are not known . Mitochondrial
permeability changes during cell death are regulated by
cellular Bcl-2 family proteins . Members of the cellular
Bcl-2 protein family either promote cell death and trigger
release of pro-death factors from mitochondria, or inhibit
this process to secure cell survival. However, the bio-
chemical functions that explain their anti- and pro-death
functions remain unknown. Many viruses also encode
Bcl-2 homologues that potently inhibit apoptosis and
often localize to mitochondria (reviewed in [7,8]). Unlike
cells, viruses lack pro-apoptotic Bcl-2 proteins, and clea-
vage by caspases or deletion of their N-termini fails to
convert viral Bcl-2 proteins into killers . Thus, viruses
capture and modify host cell functions to serve the virus.
Additional viral factors that are unrelated to the Bcl-2
family have become the focus of new research. Here we
review recent work on two viral regulators of cell death
encoded by human pathogenic viruses, the anti-apoptotic
vMIA protein of human cytomegalovirus and the pro-
apoptotic Drosophila Reaper-like protein encoded by
bunyaviruses. The viral Reaper proteins provide the first
link between vertebrate death pathways and this well-
known pro-death factor in flies. The ability of vMIA to
alter mitochondrial function and morphology provides a
new window into those mitochondrial functions involved
in programmed cell death. Thus, viruses have developed
multiple strategies involving mitochondria to regulate
programmed cell death (Table 1).
Current Opinion in Cell Biology 2003, 15:700–705 www.current-opinion.com
Viral reaper proteins
Caspases contribute to apoptotic cell death by cleaving
key protein substrates inside the cell . Although these
proteases clearlypromote cell death, their most important
contribution is arguably to promote disposal of cell
corpses and apoptotic bodies. Thus, caspases facilitate
packaging of the cell’s remnants and assist in the pre-
sentation of this neatly packaged debris for engulfment
by neighboring cells or professional phagocytes .
Despite the importance of caspases in programmed cell
death, the only known cellular caspase inhibitors are the
IAPs (inhibitor of apoptosis proteins), which were origin-
ally identified in the genomes of baculoviruses but are
now recognized in diverse species [11,12]. Caspases are
held in check by IAP proteins during developmental cell
death in Drosophila. Therefore, activation of caspases
requires the concerted effort of a set of death-inducing
proteins, including among others Reaper, Grim and Hid,
to antagonize Drosophila IAP (DIAP) [13,14]. Reaper is a
65-amino-acid protein with a variety of death-promoting
activities, including the ability to bind and displace IAP
from its caspase and promoting autoubiquitination and
can trigger cytochrome c release from vertebrate mito-
chondria in an in vitro cell extract . More recently,
Reaper was shown to inhibit cellular translation [17?,18].
amino acid sequence similarity with fly Reaper [19??].
These NSs proteins were named thus because they are
non-structural proteins (expressed from the viral genome
in cells but not incorporated into virus particles) encoded
bunyavirus genome; they are referred to here as vReaper/
vRpr. vReaper contains a 50-amino-acid region termed
the Reaper-like region (RLR) that shares sequence sim-
ilarity with the C-terminal region of Drosophila Reaper.
However, vReaper proteins lack the 14-amino-acid
N-terminal RHG motif that is conserved among the
Drosophila cell death regulators Reaper, Hid and Grim
(hence the name) as well as Jafrac2 and Sickle, and with
N-terminal motif of Drosophila Reaper binds directly to
IAP proteins and is important but not the only pro-death
function of Drosophila Reaper. Despite this apparent
deficiency, vReaper proteins appear to possess all the
functions associated with the C-terminal domain of their
Drosophila counterpart  (Figure 1).
The vReaper protein from the San Angelo bunyavirus
(SA-vRpr) efficiently inhibits protein translation in cell
extracts from rabbit reticulocytes andfrom Xenopus eggs at
levels comparable to Drosophila Reaper [17?]. In addition,
expression of SA-vRpr in mammalian cells,facilitated bya
viral IRES sequence to overcome cap-dependent transla-
tion inhibition by vReaper, resulted in severe blockage of
cellular protein synthesis. The role of vReaper proteins
during bunyavirus infections is unclear, but studies with
an engineered mutant Bunyawera virus lacking vReaper
indicate that vReaper is essential for virus-mediated inhi-
bition of host-cell protein synthesis .
Bunyaviruses infect neurons of the brain and are a major
cause of viral pediatric encephalitis in North America. A
vReaper-deficient bunyavirus replicates to lower titers in
mammalian cells and in mouse brains, correlating with
reduced virulence . To assess the function of vReaper
in neurons of mouse brains while eliminating the con-
tribution of other bunyavirus factors, vReaper from the
San Angelo virus was cloned into the neuronotropic
Sindbis virus vector. Infection of two-week-old mice with
Sindbis virus (an alphavirus unrelated to bunyaviruses)
results in a low-grade persistent Sindbis virus infection
with little or no neuronal death [21,22]. However, Sindbis
old mice, whereas animals inoculated with control viruses
all survived the infection [19??]. Analysis of brains from
animals inoculated with the recombinant Sindbis virus
encoding SA-vRpr or the vReaper from California ence-
phalitis bunyavirus (CE-vRpr) showed intense TUNEL
Viral regulators of apoptosis at mitochondria.
Viral proteinVirus Functions of viral proteins
Drosophila Reaper homologue, inhibits protein translation and triggers cytochrome
c release by a Scythe-regulated mechanism.
Binds ANT, causes mitochondrial fragmentation and decreased membrane potential,
but blocks cytochrome c release and death.
Binds ANT, induces membrane potential loss, cytochrome c release and cell death.
Localizes to mitochondria, targets cyclophilin ligand to regulate calcium and inhibit cell death.
Human immunodeficiency virus
Influenza A virus
Associates with mitochondrial PT pore, inhibits membrane potential loss and cell death.
Bcl-2 homologue in outer mitochondrial membrane, clumps mitochondria, inhibits cell death.
Binds and prevents activation of Bax and Bak to block cytochrome c release and cell death.
Causes mitochondrial fragmentation and decreased membrane potential, induces
cytochrome c release and cell death.
Viral modulators of cell death Irusta, Chen and Hardwick701
Current Opinion in Cell Biology 2003, 15:700–705
staining that was absent from control infected mice,
indicating pronounced neuronal apoptosis. Thus, these
viral reaper-like proteins are capable of promoting mam-
malian cell death even though Drosophila Reaper is a
relatively weak death factor in mammals. In contrast to
mouse brains, infection of mosquito C7/10 cells with
Sindbis virus encoding SA-vRpr did not cause pro-
grammed cell death (PM Irusta and JM Hardwick,
unpublished data). Perhaps this would be expected given
that bunyaviruses must replicate in mosquitoes to accom-
plish successful transmission to a new vertebrate host.
What is the origin of vReaper? The capture of a presumed
mosquito Reaper homologue by the bunyaviruses might
assist the virus in establishing a niche in the insect.
Interestingly, Reaper-deficient flies have insufficient
apoptosis in the nervous system, with excess neuroblasts
in the central ganglia, indicating that Drosophila Reaper is
a regulator of death in the insect nervous system [23?].
Alternatively, if vertebrates also encode a Reaper protein,
vReaper may be derived from its mammalian host in
much the same way as other viruses have captured and
modified the function of the human Bcl-2 homologue.
Like Drosophila Reaper, vReaper is able to accelerate
cytochrome c release from mitochondria in Xenopus egg
extracts, resulting in caspase activation and nuclear frag-
mentation . Drosophila Reaper appears to promote the
release of cytochrome c by binding to Scythe, which
otherwise suppresses Hsc/Hsp70-mediated protein fold-
ing [16,25]. The proposed model suggests that Scythe
sequesters a cellular factor that triggers mitochondrial
cytochrome c release, and that Reaper binding to Scythe
results in the liberation of this factor, presumably through
regulation of a chaperone function. The vReaper proteins
strongly associated with Scythe and were as effective as
Drosophila Reaper at reversing inhibition of protein fold-
ing and promoting the dissociation of the cytochrome-c-
releasing activity from Scythe [19??]. Thus, vReaper and
the C-terminal RLR domain of Drosophila Reaper appear
to induce caspase activation by the same Scythe-regu-
lated mechanism in vertebrate cell extracts (Figure 1).
Cytomegalovirus inhibitor of apoptosis, vMIA
Typical of large DNA viruses, human cytomegalovirus
(HCMV) has the ability to suppress host cell apoptosis
identify HCMV factors that inhibit apoptosis induced by
TNF-a or anti-Fas. A protein consisting of the first 163
amino acids of a larger protein encoded by the immediate
early gene UL37 (UL37 exon 1) was found to be a
powerful cell-death suppressor . This protein was
designated viral mitochondrial inhibitor of apoptosis
(vMIA) because of its predominant subcellular localiza-
tion to mitochondria. In the absence of other viral pro-
teins, overexpression of vMIA protects cells from
apoptosis induced by a variety of death stimuli including
ligation of death receptors, DNA damage, reactive oxy-
gen species, respiration poisons, and infection with an
adenovirus mutant lacking its anti-apoptotic factor E1B
19K[27–29].Itwas suggested that vMIA blocks apoptosis
at a step in the pathway where Bcl-2 proteins function.
vMIA does not share significant amino acid sequence
similarity with cellular Bcl-2 family proteins or with the
viral Bcl-2 proteins encoded by herpesviruses or other
large DNA viruses, and initial attempts to detect direct
interactions between vMIA and Bcl-2 family proteins
were not successful (but are now being revisited by
several groups). The biochemical mechanisms by which
Bcl-2 family proteins regulate apoptosis at mitochondria
or other intracellular membranes remains perplexing, but
unraveling the mysteries of vMIA will probably provide a
new perspective on the complex relationship between
mitochondria and cell death control.
Does vMIA regulate the adenine nucleotide
Apotentially interesting featureofvMIA isthepossibility
that it forms a complex with the adenine nucleotide
Release of cytochrome c
Release of unknown
native factor ‘X’
Current Opinion in Cell Biology
Proapoptotic functions of bunyavirus Reaper homologues. Bunyavirus
Reaper (vRpr/NSs) inhibits protein synthesis, which could be beneficial
for virus replication and has the potential to induce cell death through the
reduction of short-lived anti-apoptotic molecules. In addition, the
Bunyavirus Reapers can trigger the liberation of a partially characterized
factor ‘X’ in its native form from Scythe/Hsp70 complexes. This factor
then targets the mitochondria inducing cytochrome c release. Scythe
normally inhibits Hsp70 function, resulting in the sequestration of factor
‘X’. vRpr/NSs proteins, like Drosophila Reaper, appear to block Scythe-
induced inhibition of Hsp70, resulting in the generation of the
cytochrome c-releasing activity. However, vRpr apparently lack the
N-terminal motif of Drosophila Reaper that activates caspases by
interacting with IAP proteins.
Cell division, growth and death
Current Opinion in Cell Biology 2003, 15:700–705www.current-opinion.com
translocator (ANT) . ANT is an inner membrane
component of the mitochondrial transition pore complex
that is involved in the exchange of ADP and ATP
between the mitochondrial matrix and the cytosol, a
process required foroxidation phosphorylation to proceed
. On the other hand, the pore-forming ability of ANT
permeabilization that occurs following treatment with a
variety of experimental chemotherapeutic agents [27,28].
vMIA potently guards cells against apoptosis induced by
these agents, consistent with a functional interaction
between the ANT and vMIA. Moreover, both Bcl-2
and Bax were reported to bind ANT, and each had the
anticipated opposite effect on ADP/ATP exchange across
the mitochondrial inner membrane (Bcl-2 enhances while
Bax inhibits). vMIA also inhibits cooperation of Bax with
ANT to form channels in synthetic membranes, which
may provide a mechanism for protecting against perme-
ability transition [29,31]. Many unanswered questions
remain. Is there overlap between the anti-death functions
of vMIA and Bcl-2 with regard to Bax and Bak function?
and ADP/ATP exchange with regard to vMIA?
vMIA alters mitochondrial morphology
The normal tubular morphology of mitochondria in
healthy cells is due to a delicate balance between mito-
chondrial fusion and fission, a continuous dynamic pro-
cess. On the basis of studies in yeast, distinct molecular
complexes are responsible for fusion versus fission
[32,33]. A decrease in mitochondrial membrane potential
or treatment with various cell-death stimuli including
staurosporine, ceramide, etoposide or overexpressed
Bax or Bid appear to inhibit fusion while fission proceeds.
The result is that all the mitochondria in a cell become
dramatically fragmented [34,35]. A causal role for mito-
chondrial fission in cell death is suggested by studies with
Drp1, a mammalian homologue of yeast Dnm1 that is
required for mitochondrial fission in Saccharomyces cerevi-
siae. Overexpression of a dominant negative mutant of
Drp1(K38A) not only inhibits mitochondrial fission but
also delays cytochrome c release, mitochondrial mem-
brane depolarization and cell death in various apoptotic
paradigms . Furthermore, a death stimulus causes the
predominantly cytosolic Drp1 protein to translocate to
mitochondria and colocalize with Bax and Bak in clusters
at mitochondrial constriction sites . Consistent with
this idea, we have found that Bcl-xL inhibits mitochon-
drial fragmentation (Y Fannjiang and JM Hardwick,
unpublished data). Similarly, we observed that overex-
pression of the Epstein-Barr-virus anti-apoptotic Bcl-2
homologue BHRF1 causes mitochondrial morphology
changes including clumping and long tubules, suggesting
enhanced fusion  (B Polster and JM Hardwick,
unpublished data). However, excessive mitochondrial
fragmentation per se is apparently not sufficient to trigger
cell death, given that mammalian and yeast cells defec-
tive for mitochondrial fusion as a result of a deficiency in
yeast Fzo1 (fuzzy onion) or human Mfn (mitofusin) can
still survive . Therefore, we suggest that mitochon-
drial fission in healthy cells is likely to be molecularly and
biologically distinct from mitochondrial fission during
programmed cell death (Y Fannjiang and JM Hardwick,
vMIA also alters mitochondrial morphology. But, contrary
to expectation for an anti-apoptotic factor, vMIA expres-
sion in human fibroblasts appears to promote mitochon-
drial fission (or inhibit fusion), resulting in a dispersed
punctate mitochondrial pattern, yet vMIA still protects
these cells from apoptosis [39?]. Two minimal functional
domains of vMIA arerequired for its cell-death-inhibitory
capability, the N-terminal mitochondria-targeting se-
quence and amino acids 115–130. These regions are both
sufficient and necessary to induce the mitochondrial
morphology changes. Again contrary to cell-death dogma,
but consistent with the increased fragmentation of mito-
chondria, cells expressing high levels of vMIA have
reduced MitoTracker staining, implying a reduced mem-
brane potential. It will also be interesting to determine
the effect of vMIA on the subcellular localization of Drp1
and Bax. Nevertheless, vMIA, like other viral regulators
of apoptosis, is likely to provide an informative tool to
further dissect cellular mechanisms.
Even more poorly understood than the actions of the
Epstein-Barr virus BHRF1 and the bunyavirus Reaper
proteins are the mechanisms by which these cell-death
regulators contribute to viral pathogenesis in their human
hosts. The connection between the bunyavirus Reaper-
like proteins and the clinical symptoms of encephalitis
patients remain a mystery, but viral Reaper is a logical
culprit. Even more incompletely known are the molecular
and pathogenic mechanisms for other viral factors known
potently pro-apoptotic influenza virus PB1-F2 localizes to
potential . Like HIV Vpr, PB1-F2 can form pores in
membranes . Hints that PB1-F2 will be important in
an inactivating point mutation in PB1-F2. This virus has a
the myxoma poxvirus M11L protein and the Kaposi’s
sarcoma-associated herpesvirus (KSHV/HHV8) protein
K7 both appear to localize to mitochondria [42–44]. While
both of these proteins inhibit cell death, their stories are
still emerging and promise to be intriguing.
We thank the National Institutes of Health for supporting RO1 grants
NS34175, NS37402 and CA73581. We also thank members of the Hardwick
and Kornbluth laboratories for insightful conversations.
Viral modulators of cell death Irusta, Chen and Hardwick703
Current Opinion in Cell Biology 2003, 15:700–705
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