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Annu. Rev. Phytopathol. 1998. 36:393–414
c 1998 by Annual Reviews. All rights reserved
Copyright °
PROGRAMMED CELL DEATH
IN PLANT DISEASE: The Purpose
and Promise of Cellular Suicide
D. G. Gilchrist
Department of Plant Pathology and the NSF Center for Engineering Plants for
Resistance Against Pathogens (CEPRAP), University of California, Davis,
California 95616; e-mail [email protected]
KEY WORDS:
apoptosis, lesion mimics, hypersensitive reaction, ceramide, cell cycle
Truth is seldom pure and never simple.
Oscar Wilde
ABSTRACT
The interaction of pathogens with plants leads to a disruption in cellular homeostasis, often leading to cell death, in both compatible and incompatible relationships.
The mechanistic basis of this cellular disruption and consequent death is complex
and poorly characterized, but it is established that host responses to pathogens are
dependent on gene expression, involve signal transduction, and require energy.
Recent data suggest that in animals, a genetically regulated, signal transduction–
dependent programmed cell death process, commonly referred to as apoptosis, is
conserved over a wide range of phyla. The basic function of apoptosis is to direct
the selective elimination of certain cells during development, but it also is a master template that is involved in host responses to many pathogens. Programmed
cell death in plants, while widely observed, has not been studied extensively at
either the biochemical or genetic level. Current data suggest that activation or
suppression of programmed cell death may underlie diseases in plants as it does
in animals. This review describes some of the fundamental characteristics of
apoptosis in animals and points to a number of connections to programmed cell
death in plants that may lead to both a better understanding of disease processes
and novel strategies for engineering disease resistance in plants.
393
0066-4286/98/0901-0393$08.00
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INTRODUCTION
Cellular Suicide
Suicide, in human terms, is intellectually difficult to accept and generally viewed
as impulsive or irrational and inconsistent with balanced behavior. Suicide in
cellular terms, however, is exactly the converse: it is pervasive, organized,
rational, and leads to organismal balance, both in development and in response
to stress. To achieve and maintain homeostasis, cells in multicellular organisms
self-destruct when they are no longer needed or if they are damaged (3). This
is accomplished by activation of genetically regulated cell suicide machinery
that requires the active participation of the cell in a suicide process known as
programmed cell death (PCD) (6, 62, 78, 104). In contrast to PCD, necrosis
is most commonly defined as cell death that results from exposure to highly
toxic compounds, severe cold or heat stress, or traumatic injury that leads to
immediate damage to membranes or cellular organelles (19). The key distinction
is that necrosis does not require the active participation of the cell in its own
demise. In retrospect, the lethal logic of PCD has long been recognized, but
only recently has extensive evidence for a conserved genetic template appeared
that responds to a range of inter- and intracellular factors.
Moreover, PCD is now recognized as a common cellular default mechanism
in that almost all cells appear to possess the machinery necessary to carry out
the terminal steps of death. Evidence for this includes the constitutive presence
of many proteins required for PCD in nucleated animal cells beginning with
the zygote (106, 117). In fact, the nucleus does not appear to be required in
some cases as anucleate cytoplasts undergo PCD when treated with the protein
kinase inhibitor staurosporine (61). The death program is triggered during developmental transitions in situations that lead to sculpting of structures, deleting
unneeded structures, controlling cell numbers, eliminating abnormal or harmful
cells, and producing differentiated cells without organelles (61). For example,
PCD eliminates cells between tadpole tails (66) and between developing digits
such as fingers and toes (62). It occurs where epithelial sheets invaginate and
pinch off to form tubes or vesicles like the vertebrate neural tube or lens (62).
In the vertebrate nervous system, up to half of new nerve cells die by PCD,
apparently to match their numbers to the number of target cells they innervate
(91). These are but a few examples among many that underscore the prevalence, diversity, and importance of programmed cell death in the development
of organized tissues in eukaryotic organisms.
Conversely, the existence of such a default death program represents a point of
vulnerability for the organism if it is inappropriately triggered or inappropriately
suppressed during development or in disease situations (30, 31, 102, 107, 110,
119). It is this potential for co-option by pathogens that renders the consideration
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of programmed cell death a significant issue for plant and animal pathologists.
Examples such as those indicated above make both the genes that define the PCD
program and the mechanisms that keep it from occurring at random compelling
research targets for cell biologists and geneticists (62). The need for cells to
manage a default programmed cell death pathway(s) suggests a number of
fundamental questions for cell biologists that are currently under intensive
study in many laboratories. Why do cells die when and where they do during
development? How are the PCD genes regulated to ensure transcription or
activation of the gene product at the appropriate or necessary time and place?
What are the PCD signals, how are they propagated, and what limits the spread
of these signals?
PROGRAMMED CELL DEATH
IN ANIMALS: APOPTOSIS
Characteristics of Apoptosis
One reason why research had not focused on programmed death templates until
recently was the lack of evidence for a common mechanism, highly conserved
and widely distributed, that regulated cellular homeostasis through the selective
elimination of certain cells. The origin of active study of PCD began in 1972
with the publication of a landmark paper that introduced the term apoptosis (68)
and described fundamental characteristics of apoptosis as “a basic biological
phenomenon with wide-ranging implications in tissue kinetics” (68). The term
apoptosis was derived from two Greek roots: apo (away) and ptosis (to fall, also
a medical term referring to the drooping of eyelids) that was used to describe
petals falling from flowers or leaves from trees. Kerr and colleagues described
several epithelial cell types that underwent orderly death during development.
These included cells that died owing to withdrawal of survival signals and cells
that had been exposed to toxins. The creative synthesis of their observations
led to the conclusion that in each of these cases, the dying cells exhibited
consistent morphological features during death and that cell deletion played
a complementary but opposite role to mitosis in the regulation of animal cell
populations (67, 68).
Later, other scientists recognized the existence of a series of morphological
and biochemical hallmarks of apoptosis in animals (108, 109). Animal cells
undergoing apoptosis exhibit shrinkage, loss of cell-to-cell contact in organized
tissues, and the orderly fragmentation of nuclear DNA at internucleosomal
sites, which is then organized into sharply defined membrane-bound apoptotic
bodies. In animal cells, these apoptotic bodies are taken up by adjacent cells
and degraded within minutes to hours (9). Hence, the function of the apoptotic
bodies is thought to be the protection of neighboring cells from damage due to
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leakage of toxic cellular contents of the dying cell until resorption is completed.
Internucleosomal cleavage of DNA is catalyzed by an endogenous calciumdependent endonuclease that generates 180-bp multiples of these fragments
(Figure 1). Multiples of these units can be resolved by gel electrophoresis
as a laddered pattern of DNA that corresponds to the nucleosomal fragments
(108). Fragmentation of DNA during apoptosis also can be detected in situ
by reagents that react with the exposed 30 hydroxyls on the nucleosomal units
(39). The assay procedure, commonly referred to as the TUNEL assay, involves
end labeling of the nucleosomal DNA fragments by terminal deoxynucleotidyl
transferase with UTP conjugated to a detectable marker (44). The TUNEL
assay is capable of detecting limited amounts of DNA fragmentation during
apoptosis (75). However, this assay must be used with caution since DNA
degraded during nonapoptotic cell death and during the fixing of tissue also
may give positive reactions (45, 115).
Evolution of Research on Apoptosis
What has made this topic so compelling to so many today? Recognition of the
fundamental importance of apoptosis was not immediate. In fact, it took nearly
two decades after the landmark publication by Kerr and colleagues (68) for the
term apoptosis and its biological ramifications to be fully appreciated. Since
1972, however, the number of publications related to apoptosis has increased
exponentially every year (93). Today, apoptosis is not only accepted as a universal mechanism regulating cellular homeostasis in animals, it is also driving
a veritable biological revolution in basic research in cell biology and medicine.
This has occurred for several reasons. First, there has been an explosion of
discoveries in laboratories worldwide in resolving the structure and function of
genes, signal molecules, and signal transduction pathways regulating apoptosis.
Second, it has been recognized that the functional machinery of apoptosis, both
genes and signaling events, is highly conserved from nematodes to insects to
humans, albeit with subtle differences in the actual mechanisms. Third, it has
now become clear that the dysregulation of apoptosis is the basis of many human
diseases (Table 1). The convergence of these pieces of scientific information
has now placed both the fundamental and the practical study of apoptosis in the
forefront of biological and pharmaceutical research (25, 62, 93, 111, 123).
Role of Apoptosis in Animal Disease
In what may seem at first to be a paradox, apoptosis plays a key role in both degenerative and proliferative diseases (Table 1). Elucidation of controlling genes
and signaling pathways has provided evidence for an evolutionarily conserved
link between maladies ranging from Alzheimer’s disease (112) to cancer (107).
It is perhaps intuitive that any process that is highly conserved to maintain
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Figure 1 Representative genes, signaling pathways, and other death-dependent changes associated with programmed cell death in animals.
See text for details.
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Table 1 Examples of human diseases where dysregulation of apoptosis is believed to play
an important role in the syndrome
Immune system
Autoimmune diseases; Lupus, Graves disease, rheumatoid arthritis,
AIDS, Type I diabetes
Cancer related
Lymphoma, leukemia, colon cancer, solid tumors
Neurological system
Alzheimer’s disease, Lou Gehrig’s disease, Parkinson’s disease,
Huntington’s disease, multiple sclerosis
Viral diseases
Cowpox virus, Adenovirus, Epstein-Bar virus
order can result in harsh consequences for an organism when circumstances
beyond the control of the organism disrupt that order. For example, excessive
cell death can lead to impaired development and degenerative diseases (99),
whereas insufficient gene-directed cell death can lead to cancer (35), permit
viral infections (17, 102), and contribute to autoimmune diseases (88). Helper
T cells undergo apoptosis in AIDS, and neurons die by apoptosis in Alzheimer’s
disease, Parkinson’s disease, Huntington’s disease, and Lou Gehrig’s disease
(31). In disease situations where immortalization or extensive proliferation of a
cell line occurs, such as in cancer or virus infections, the expression of various
proto-oncogenes and virus-encoded genes (Figure 1; adenovirus E1A, SV40
Large T antigen) that actively suppress apoptosis appears to be widespread
(12, 16, 17, 76). Hence, the genes and signal molecules involved in apoptosis
(2, 123) have become widely sought targets for therapeutic manipulation in both
degenerative and proliferative diseases of animals and humans (20, 25, 30, 107),
including diseases of the immune system (22).
Regulation and Propagation of the Apoptotic Signal
A central question in the field of PCD is whether an irreversible commitment to
death leads from a common biochemical pathway to the morphological features
of apoptosis (47). The general feeling at this time seems to favor the view that
there are several pathways capable of being invoked in a cell-specific fashion
with different final morphologies. This means some pathways may lead to the
typical morphology of apoptosis whereas others may have a different final morphology (47), yet the outcome is the same. A number of factors are involved
in the triggering and propagation of apoptosis in animals (Figure 1). Among
these are cell surface receptors, transmembrane domains, intracellular proteins
involved in propagation of death signals (death domains), second messengers
including inositol triphosphate and ceramides, Ca2+ fluxes, reactive oxygen
species, cell cycle regulating factors (cyclins and coupled cdc kinases), and
proteins that act as either suppressors (e.g. Bcl2, iap) or activators (e.g. Bax) of
cell death (101, 104, 105) (Figure 1). There seem to be two central connections
to most forms of PCD: an arrest of the cell cycle and the activation of a protease
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cascade. Members of the family of cysteine proteases related to the interleukin
1-β converting enzyme (ICE) have been shown to be necessary for programmed
cell death in a number of biological systems (82). The activation of these specific proteases, now referred to as caspases, from proenzymes (ProICE), is now
recognized as a key biochemical marker of apoptosis, often detected by their
action on specific substrates (94). The fact that a number of resistance genes
cloned recently from plants, including the N gene from tobacco, have sequence
similarity to the Toll gene or interleukin receptor suggests a possible connection
to signal response in plants to those involved in PCD in animals (118) (Figure 1).
Role of the Cell Cycle in Programmed Cell Death
Morphological, biochemical, and gene-expression studies have suggested that
apoptosis may represent a disordered type of cell cycle progression (Figure 1).
Several lines of reasoning have led to this conclusion (65). Cells undergoing
mitosis or apoptosis lose cell volume, condense their chromatin, and disassemble the nuclear lamina in a morphologically similar fashion. Manipulation of
the cell cycle may either prevent or induce apoptosis (34). The ability (susceptibility) of cells to undergo apoptosis following reception of a “death” signal
often depends on the stage of the cell cycle or the presence of specific cell cycle checkpoint–regulating compounds, including cyclins and cyclin-dependent
kinases (cdk) (69). Phosphorylation and solubilization of nuclear lamins have
been observed in some apoptotic animal models. The induction of the cell
cycle regulating p34cdc2 kinase activity during apoptosis and a dependency on
the activity of p34cdc2 kinase have been reported (103). It is well established
that p34cdc2 activity is elevated as cells traverse the G2/M transition and that this
protein is a universal regulator of mitosis in eukaryotic cells (47) (Figure 1).
Arrest or disruption of the cell cycle is a common feature of cells that eventually undergo PCD (14, 15, 79). Arrest at the G1/S checkpoint appears to be a key
point (14). The signals, receptors, and signal transduction pathways appear to
be functionally conserved from bacteria to fungi to plants and animals (3, 110).
Hence, any cell in the path of the signaling wave may receive and respond
to that signal by undergoing arrest and, upon failing escape the impact of the
signal, will be triggered to undergo PCD. A recently described example of a
universally conserved gene that appears to play a key role in regulation of the
cell cycle, cell death and that appears to play a role in the suppression of cell
death by virus encoded factors is the retinoblastoma gene (Rb) (65) (Figure 1).
Rb activity is regulated by phosphorlyation and dephosphorylation reactions
that are mediated by various signals including expression of other genes and
second messengers like ceramide (see below). The E1A and E7 genes, encoded
by animal viruses, bind to Rb, alter regulation of the cell cycle and lead to the
suppression of PCD during viral replication. Rb has recently been identified
in plants and the RepA protein, encoded by plant gemini viruses also can bind
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to Rb. This connection between plant virus genes and Rb suggests that the
virus replication scenario, at least in these viruses, may act in a fashion similar
to animal viruses although this has not been established. If the signals and
signaling pathways that arrest animal and plant cells at specific stages in the
cell cycle originated with single cell organisms, then the signals and receptors
that lead to cell death could conceivably be conserved with cross-kingdom responsiveness from bacteria to fungi to animals and to plants. Using the same
logic, it also may be true that an invading pathogen could send signals to host
cells that trigger cell cycle arrest and thus lead to the induction of cell death
during disease.
Ceramide Signaling and Apoptosis
The signals that regulate apoptosis in animals are a topic of extreme interest.
Several signals were noted earlier but among the most intriguing is the recent and novel involvement of ceramide-related compounds in affecting both
development and apoptosis. The linkage of ceramide signaling to apoptosis,
cancer, and degenerative disease in animals is now driving a rapidly emerging
novel area in signal transduction in animal biology (13, 54, 55, 80, 90), wherein
ceramide-linked signaling pathways are studied as critical second-messenger
systems (54, 70) (Figure 2). For example, sphingolipids have been implicated
as playing a direct role in cell contact, growth, and differentiation as well as
in influencing the proliferative potential of mammalian cells by induction or
suppression of apoptosis (reviewed in 54). Sphingolipids also have been linked
to increased superoxide formation and calcium influx in neutrophils (122).
Fumonisin B1 (FB1), a sphinganine-analog mycotoxin (Figure 3), alters cell
morphology, cell-cell interactions, the behavior of cell surface proteins, protein kinase activity, and cell growth and viability (as reviewed 80), in addition
to inducing apoptosis in animal cells (115) (discussed later). Results from our
laboratory and others suggest that plants and animals may share a heretofore unrealized connection to apoptosis through ceramide-based signaling pathways.
If ceramide signaling is widely conserved, it could provide a new biochemical
link between programmed cell death and disease responses in plants.
PROGRAMMED CELL DEATH IN PLANTS
Programmed Cell Death in Plant Development
Although apoptosis in animals was likened to senescence of plant leaves (68),
evidence of genetic controls and signaling molecules in plants undergoing PCD,
analogous to those now widely studied in animals, has emerged only recently
(40, 97). This is in spite of the recognition that programmed cell death regimes
occur in numerous situations in plants (see reviews by 7, 37, 38 46, 92). Examples of programmed cell death in plant development include the timely death of
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Figure 2 Structural relationships between sphinganine, ceramide, and the sphinganine analog
mycotoxins, Fumonisin B1 and AAL toxin TA.
petals after fertilization, during diploid parthenogenesis (56), the development
of tracheary elements (37, 38, 51, 84, 115), and senescence of leaves (8). The
cell death associated with tracheary element formation serves as a model system for analysis of specific cells clearly targeted for death but not destruction
(36–38).
One of the major difficulties in detecting morphological markers of apoptosis
in cells, or in those cells that are preparing to undergo PCD, is that the process is
localized, generally to a few cells, and is not synchronized. Given the speed of
the process in animals (minutes to hours) (75), observation of the various steps
in the process in plants is limited by the ability to predict which cells are destined
to undergo PCD and when it will begin. These hurdles may be overcome by
examining tissues in which the process is ongoing continuously. Situations
where cell death is semisynchronized and where sufficient numbers of cells
regularly undergo a form of PCD include root cap cells and aleurone cells.
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Figure 3 Ceramide biosynthetic pathway. Ceramide synthesis in plants and animals is initiated by
condensation of palmitoyl-CoA and serine. Sphinganine analog mycotoxins, FB1 and TA, inhibit
ceramide synthase and trigger apoptosis in plant and animal cells.
The programmed death of aleurone cells in barley during germination displays several characteristics associated with apoptosis (116). TUNEL staining
of aleurone cells that had been triggered to die indicated that nuclear DNA in
the cells undergoes fragmentation starting near the embryo. This fragmentation
proceeds outward in a time-dependent manner in vivo and under osmotic stress
in isolated cells in vitro. The visualization of DNA fragmentation precedes
visible signs of death. Abscisic acid inhibits the aleurone cell death and DNA
fragmentation both in vivo and in vitro. Okadaic acid, a protein phophatase
inhibitor that suppresses apoptosis in some animal systems, also inhibits the
death of aleurone cells (72, 116).
The root cap consists of living parenchyma cells derived continuously from
the apical meristem (33). As new cells are produced in the interior, those on the
periphery of the root are shed in a very orderly manner, reminiscent of Kerr’s
original connection of the term apoptosis to cell death as a natural programmed
process (68). Cap cells of fresh onion and tomato root tips, double stained by the
TUNEL assay and a DNA stain, revealed that nuclear DNA in cells throughout
the root sections remained intact until the cap cells reached the surface of the
root. The region of TUNEL-positive cells was restricted to the outermost 1–3
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cells of the root cap (115). The appearance of nuclear DNA changed from a
compact circular form to elongated TUNEL-positive structures that eventually
took on the form of numerous membrane-bound circular bodies that migrated
to the periphery of the dying cell. The formation of these bodies appeared to be
the final step reached before a cell is shed from the root cap. The morphology
of PCD in aleurone and root cap cells confirmed the conservation of at least the
terminal phases of the apoptotic process in plants.
Although there are recent examples where many of the stereotypical hallmarks of apoptosis have been observed in plants, they have clearly not been
detected in all cases where programmed death occurs (7, 37, 38, 52). Several
explanations are plausible. First is that the death of specific cells, while programmed, occurs by mechanisms that do not invoke an apoptotic template and
therefore the markers will not be present. Second is the fact that programmed
cell death in plant tissues, as in animal tissues, is initiated in a few cells and
the wave of death that may spread into surrounding cells is asynchronous. This
results in immense difficulty in detecting common controlling events and a serious dilution of key signal molecules or other markers when extracts are made
from a mix of responding and nonresponding cells. Notice also is taken of the
fact that all programmed cell death in animals does not proceed by a strictly
apoptotic process, nor do all the typical hallmarks appear in all cases where
apoptosis is involved (21, 100).
Programmed Cell Death in Plant Disease
Cell death and disease in plants are intimately connected in several ways. As in
animals, localized cell death in plants appears to play opposite roles in disease,
where cell death is both a symptom of susceptibility (115) and of resistance,
at least in the case of the hypersensitive resistance response (HR) where cell
death is a characteristic phenotype (43). A number of recent reviews have dealt
with possible connections between plant disease and PCD associated with the
HR (23, 24, 40, 48, 84).
There is recent evidence of morphological markers of apoptosis associated
with cell death in plant disease–related circumstances. The markers include
TUNEL-positive cells, DNA ladders, and apoptotic-like bodies, as have been
reported in plant disease–associated death and in response to arachidonic acid,
which is an elicitor of the HR (115). Positive TUNEL reactions and DNA
ladders were reported by Ryerson & Heath (98) in cowpea leaf cells exhibiting
HR resistance to Uromyces vignae. Studies by Lam and coworkers detected
the presence of TUNEL-positive cells in tissues expressing HR in response to
infection by tobacco mosaic virus and following the transgenic expression of
a bacterial proton pump (84–86). The significance of the activation of proton
pump ATPase may lie in the fact that it has also been shown to be part of early
defense responses of plants to pathogens (5).
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Mycotoxins Connect Apoptotic Morphology
and Ceramide Signaling
A connection between apoptosis and ceramide signaling in plants and animals was revealed in concurrent studies with animal and plant cells exposed
to sphinganine analog mycotoxins (SAMs) (114, 115). The SAMs include the
fumonisins and AAL toxins, a recently discovered class of mycotoxins that
are synthesized by Fusarium moniliforme and strains of Alternaria alternata
(11, 89), respectively. The AAL toxins consist of a family of disease-dependent
host-specific toxins (11) associated with the stem canker disease of tomato
caused by A. alternata f. sp. lycopersici (18, 41, 120). Fumonisin B1 (FB1) induces a variety of responses in the challenged animals including neuro-, renal-,
or has been reported to be a virulence determinant in plant disease, and also
induces a variety of responses in challenged animals, including heptatoxicosis
and neoplasms as well as cell death (26, 32, 80). AAL toxin (TA) has been
reported to have similar effects where tested in animal cells (120).
The induction of cell death in both animal and plant cells by FB1 and TA
occurred at similar toxin concentrations (10–50 nm) and followed similar time
frames (12–24 h). Morphological markers, characteristic of apoptosis, were
observed in both tomato and green African monkey kidney (CV-1) cells. The
key markers included TUNEL-positive cells, DNA ladders, Ca2+-activated nucleosomal DNA cleavage that was inhibited by Zn2+, and the formation of
apoptotic-like bodies (114, 115).
With respect to mode of toxin action, ceramide signaling, and PCD, several
reports have now established that exposure of animals and cultured animal cells
to SAMs leads to altered sphingolipid metabolism, as evidenced by rapid and
dramatic changes in sphingoid bases and ceramide (1; reviewed in 80). The
structural relationship of SAMs to sphinganine, an intermediate in the biosynthesis of ceramides, sphingomyelin cerebrosides, gangliosides, and sulfatides,
is the basis for current models linking mode of action to alterations in the
synthesis of sphingoid bases (Figure 2). One site of metabolic disruption is
the reaction catalyzed by sphingosine N-acetyltransferase (ceramide synthase),
wherein FB1 was first reported to be a potent competitive inhibitor of this enzyme from liver and brain microsomes, as well as in several mammalian cell
lines (81, 113) (Figure 3).
An increase in sphinganine, consistent with inhibition of ceramide synthase in
vivo, is commonly observed following exposure to SAMs. Physiological studies have confirmed that animals fed fumonisins at toxic concentrations show
changes in levels of sphinganine and sphingosine consistent with in vivo inhibition of ceramide synthase (96, 113). Similar observations have been reported
for toxin-treated plant cells (1). Later it was shown that both FB1 and TA inhibit
ceramide synthase in rat hepatocytes (81), and in microsomal preparations from
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green tomato fruit (41). In tomato tissues, there is a significant and equivalent
inhibition of the enzyme at 20 nM, with an I50 in the range of 35–40 nM for
both AAL-TA and FB1 (41). Taken together, the data suggest that the induction
of apoptotic-like cell death by the SAMs in plant and animal cells is caused by
alterations in ceramide metabolism.
The death induced by SAMs appears to show one additional linkage to characteristics associated with cells undergoing an apoptotic form of cell death. As
indicated earlier, disruption of cell cycle progression is frequently associated
with cells undergoing apoptosis (69, 79). Treatment of CV-1 cells with FB1
resulted in G1 arrest. In contrast, CV-1 cells transformed by the simian virus
40 (SV40) large T-antigen (COS-7) are not sensitive to the same levels of FB1
or AAL-TA that kill CV-1 cells (114). Since large T-antigen has pleiotropic
effects on cell cycle regulation and induction of apoptosis, it may overcome the
apoptotic properties of FB1 by preventing cell cycle arrest (Figure 1). Taken
together, the current data suggest that the action of the SAMs in inducing cell
death is consistent with an apoptotic process that involves ceramide signaling
and disruption of the cell cycle.
There are many reports in the literature indicating that ceramides and sphingosine derivatives are potent second messengers that trigger apoptosis and regulate
developmental processes in animals (reviewed in 54). Sphingolipid synthesis
in plants occurs by the same pathway as in animals but, by comparison, little is
known about the enzymes involved, their kinetic properties, regulatory mechanisms, or intracellular location in plants (reviewed in 77). Even less is known
about ceramides in plants, although one report indicated that 17% of the lipids
in the tonoplast of mung bean consists of ceramide monohexoside (124). It
appears now that plants also may utilize ceramide-linked signaling systems, at
least in some stress responses, as noted above. While the complexity of cellular responses observed and the direct connections between toxicity of these
mycotoxins and ceramide-mediated responses are unresolved, they should be
useful tools for deciphering the role of ceramides in development and disease.
If ceramide signaling is conserved in plants as in animals, the role of ceramide
second messengers in plant disease deserves further study in relation to both
the induction and the suppression of PCD in plant disease.
Death in the Hypersensitive Resistance Response:
Cause or Consequence?
As indicated earlier, cell death in plant tissues responding to pathogens occurs
not only in susceptible reactions but also in resistant responses. In particular, cell death has been assumed to play a role is the previously mentioned
HR that is characteristic of several incompatible plant-microbe interactions.
HR-linked cell death requires active plant metabolism and depends on the activity of host transcriptional machinery (57). Included among the resistance
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markers expressed in cells undergoing an HR cell death are the expression of
so-called pathogenesis-related proteins, generation of reactive oxygen intermediates, rapid influx of calcium, production of phytoalexins, and the cross-linking
of components of the cell wall (29, 53, 64). In several studies of inducible host
responses to infection by incompatible strains of bacterial and fungal pathogens
with the HR phenotype, the affected host cells show dramatic changes in calcium influx and generation of an oxidative burst. Both hydrogen peroxide and
superoxide anion have been suggested as factors important in the execution of
infected cells by the HR (5, 60, 74), although the active oxygen response alone
may not be sufficient to cause the HR (42). Many of these same changes are
associated with the induction of apoptosis in animal cells (69).
The sum of extensive research in this area is that, although these chemical
factors have been shown to be toxic to certain pathogens in vitro and their
induction is correlated with resistance in vivo, the exact mechanistic role that
any or all of them play in resistance is not known. With respect to the association
of cell death as a common phenotype of the HR, it was noted earlier in this
review that morphological markers of apoptosis have been reported in lesions
associated with the HR (84–86, 98, 115). This suggests that activation of PCD
pathways may be involved in the resistance response. Regardless of whether
PCD pathways are co-opted in the HR, it remains to be proven that cell death
has a determinative role in resistance. The unresolved question is whether the
failure of the pathogen to extend invasion beyond the point where cell death
is observed is due to host cell death or whether the spread of the pathogen is
arrested before the affected host cells die and death is an anticlimax (58, 87).
Stated differently, even if PCD pathways are activated in the HR, it remains
to be proven that cell death has a determinative role in resistance. Resolution
of this issue will require isolation and characterization of genes regulating cell
death in the HR. Only then will it be possible to assess the functional role in
resistance of cell death and the biochemical changes that are associated but not
definitely proven to be required for resistance.
Lesion Mimic Mutations, Programmed Cell Death,
and Plant Disease
Plants express cell death–initiating mutations at defined genetic loci in many
species of commercial plants, including tomato, maize, and barley (121), as well
as Arabidopsis thaliana (27, 50). These genetic lesions are controlled by single
genetic loci and have been designated lesion mimic mutations. Similarities between the phenotypes associated with these examples of genetically regulated
cell death in plants and the apoptotic process in animals have been noted by several authors (4, 27, 46, 49, 50, 73, 86). In the case of several of these genes, resistance, at least to some pathogens, seems to be enhanced in plants capable of expressing genetic lesions, and this resembles a wild-type resistance response (87).
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For example, the Arabidopsis lesion mimic mutant lsd1 shows both enhanced
expression of disease-resistance markers and increased resistance to bacterial
and oomycete pathogens when lesions are present (27). A second mutation in
Arabidopsis, acd2, developed spontaneous lesions in the absence of pathogens
and expressed an HR phenotype in otherwise healthy areas of the plant when
distal tissues were inoculated with either virulent (cause disease) or avirulent (trigger HR) bacterial pathogens (50). In contrast, wild-type plants lacking
these recessive mutations express the HR phenotype only when inoculated with
avirulent strains of the pathogen. Barley plants expressing the recessive ml-o
alleles that condition broad-spectrum resistance to all known races of Erysiphe
graminus f. sp. hordei encode a putative transmembrane protein (10) that plays a
critical role in the host response. In the absence of the pathogen and at low temperatures, the mlo plants sporadically show spontaneous formation of lesions
(121). It is speculated that in the mlo plants there is either a hypersensitized
sensor of cell homeostasis responding to unknown environmental stimuli or the
pathway is prematurely activated to trigger cell death in a fashion related to
senescence. Interestingly, the cell death is localized, occurring in only a few
cells, and does not spread over time.
Recently, Kosslak et al (71) reported a soybean root necrosis (rn) mutation
that causes a progressive browning of the root soon after germination. The
appearance of cell death in the rn mutants is associated with accumulation of
pathogenesis-related (PR) factors, including the phytoalexin glyceollin and the
group 2 anionic peroxidases. Homozygous rn plants also showed resistance
to root infection by Phytophthora sojae that correlated with the onset of the
browning reaction (71). Interestingly, the resistance expressed in the roots was
not systemically transferred to hypocotyl tissue, which remained susceptible
to P. sojae, unlike several of the aforementioned Arabidopsis lesion mimic
mutants.
The recent map-based cloning of the LSD1 gene adds another dimension to
the death process initiated by lesion mimic genes in relation to the involvement
of reactive oxygen in cell death and plant response to disease (28). In this
case, reactive oxygen intermediates may play a role in mediating the response
associated with the alleles of the lesion mimic mutation. LSD1 appears linked
to a superoxide-dependent pathway and negatively regulates a plant cell death
pathway at the level of transcription. In the plants carrying the lsd1 mutation,
the presence of superoxide is a necessary and sufficient signal for cell death
(28, 87). The mechanism by which the LSD1 gene functions could involve either
the repression of a prodeath pathway or the activation of an antideath pathway.
Whether the mutations that give rise to these lesions are in pathways that determine cell death in the HR response or in lesions occurring in compatible
plant-microbe interactions is not known. In the case of the lsd and acd mutations in Arabidopsis, there is a corresponding increase in the expression of
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a number of defense-related genes in plants expressing the lesion mimic phenotype and an increased resistance to some pathogens (27, 63, 87). Still, the
data are not conclusive on the matter of direct biochemical and morphological
links between cell death associated with lesion mimics and disease-related cell
death. Additional biochemical and signal transduction linkages will need to be
resolved before this interesting association can be defined at a functional level.
PCD Targeted Therapies: The Next Big Thing
in Biotechnology
Therapeutic modification of gene expression or signaling pathways involved
in apoptosis is a rapidly expanding area in animal and human health research.
However, the selective therapeutic regulation of PCD for purposes of disease
modulation presents numerous challenges while offering tremendous potential
rewards (28, 83). Do similar promises and challenges also exist for plant biologists and plant pathologists? Current information would suggest that they do
have tremendous potential, but, in truth, translation into practical applications
may be neither pure nor simple. Clearly the complete suppression of PCD in
plants or animals would be developmentally unacceptable. Hence, whatever
modification is imposed on PCD pathways to alter development or the progression of disease, it will have to be limited or site specific. In the case of
plant diseases, the effect of either induction or suppression of PCD would be
expected to be different for obligate and nonobligate parasites. Facultative parasites able to use the contents of dead cells as a nutrient source would benefit
from inappropriate host cell death but could be thwarted if death is suppressed.
Early death of host cells before an obligate pathogen is established could serve
to limit infection, in contrast to the suppression of cell death during infection
that might favor them.
In the case of nonobligate parasites, the general result of infection is death
of tissues during colonization. Both bacterial and fungal pathogens that are
not obligately parasitic secrete toxic substances that are either necessary for
infection or facilitate infection by causing cell death in advance of the growth
of the pathogen through the affected tissue. Physiological changes in the toxinstimulated cells could trigger default genetic programs leading to cell death.
Except for the fumonisins and AAL toxins, no studies have been reported that
directly test this hypothesis.
The active suppression of default programs to eliminate cells undergoing
pathogen-induced stress (suppression of apoptosis) is a formal possibility in
plant-microbe interactions involving compatible obligate parasites, including
viruses, fungi, and plant parasitic nematodes, as well as symbiotic interactions
as with Rhizobia and endomychorrizal fungi. Similarly the existence and role
of both exogenous and endogenous inhibitors of apoptosis (IAPs) are well
documented in animals (102). For example, many animal viruses encode IAPs
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such as p35 from baculovirus and CrmA from cowpox virus that serve to block
apoptosis during viral replication (17, 95). No evidence has been reported for
IAPs in plants or pathogens but their existence is logical and warrants specific
study.
Given such scenarios, site-specific suppression (necrotrophs) or induction
(biotrophs) of PCD pathways by either genetic or chemical tactics present unexplored opportunities to alter host response to pathogens. The major challenge
lies in the characterization of the genetic and biochemical components of the
process. Analogous to animals, the confirmation, characterization, and manipulation of a gene expression–dependent cell death process in plants will require
linkage to specific genes, sets of interacting genes, or gene products that respond to the signals transduced by a range of stimuli. Directed alterations in
any of these genes and focused expression at sites of infection will be aided by
coupling to pathogen-induced promoters.
Many laboratories currently are using both genetic and biochemical approaches to identify genes and pathways involved in PCD in plants. Cloning
of genes in plants by DNA homology may not be easy even if major portions
of the apoptotic process is conserved in plants. For example, where functional
homology is conserved in animals, the homology at the DNA level between
genes regulating complementary functions is often less than 20%. Identification by differential expression is problematic because small subpopulations of
asynchronously responding cells must be analyzed against a large background
of nonresponding cells. Furthermore, the number of cells that actually complete
the stereotypical steps of apoptosis prior to metabolic collapse may represent
only a fraction of the total and thus difficult to detect. Regardless of the difficulties, the information value of characterizing the genes and signal transduction
pathways is very high for understanding and modifying plant development and
plant disease.
CONCLUSIONS
The molecular and biochemical events that occur at the sites of infection in
plants include a plethora of changes that are triggered by both host and pathogen
genes (40, 48, 58, 87). The biochemical range of plant response to pathogens
exhibits similarities to those associated with apoptosis in animals. With respect
to the nutritional and growth requirements of the pathogen, the consequences
of an apoptosis-like induction or suppression of host cell death during the
early phases of infection could determine the eventual outcome (41, 115) of
disease for both obligate and nonobligate parasites. Hence, PCD represents a
potentially vulnerable target for pathogen signals that may act to either induce
or suppress death by altered gene expression or by interfering directly with key
signal transduction pathways.
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The current information on PCD in plants indicates that the morphological
features of apoptosis can be found in contexts analogous to its appearance in
animals. This suggests that at least the terminal steps in the apoptotic process,
as characterized in animals, are conserved in plants. This does not confirm
that the signaling pathways are equally conserved. However, triggers of cell
death like the sphinganine analog mycotoxins and arachidonic acid that induce
apoptosis in animal cells lead to expression of the same apoptotic markers
in sensitive plant cells. This suggests that, at least in these cases, common
signaling pathways and regulatory genes are conserved in both animals and
plants. The opposing effects of PCD in development and disease also appear
to exist in a functional context.
However, the extent to which additional signaling pathways and functional
homologs of the controlling genetic elements of programmed cell death regimes
are conserved in plants is unresolved. Yet, since the final morphological characteristics of apoptosis have been observed in plants and complementary signal
responses appear also to be conserved in specific situations, it is likely that
many of the functional elements will be similar. It is also highly likely that
plant-specific pathways and their corresponding genes will have diverged to
account for the differences in form and function of individuals within the two
kingdoms. Regardless of the extent of similarity, the genes and signal molecules
that define programmed cell death in plants will become important targets for
both understanding and manipulating this process in development and disease.
Given the complexity and the diametric consequences of ordered death in
development and disease, the admonition of Oscar Wilde is relevant to the dialog
and discovery of the role of PCD in plant development and plant disease.
ACKNOWLEDGMENTS
Appreciation is expressed to Jim Lincoln, Bert Overduin Hong Wang, and
Richard Bostock, for helpful discussions. Portions of the research discussed
herein were supported by the NSF Center for Engineering Plants for Resistance
Against Pathogens (CEPRAP).
Visit the Annual Reviews home page at
http://www.AnnualReviews.org.
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