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The Drosophila Imd Signaling Pathway
Henna Myllymäki, Susanna Valanne and Mika Rämet
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References
J Immunol 2014; 192:3455-3462; ;
doi: 10.4049/jimmunol.1303309
http://www.jimmunol.org/content/192/8/3455
The
Brief Reviews
Journal of
Immunology
The Drosophila Imd Signaling Pathway
Henna Myllymäki,* Susanna Valanne,* and Mika Rämet*,†,‡,x
M
ulticellular organisms constantly encounter potentially harmful microorganisms. Although insects
lack an adaptive immune system in the classical
sense, it has long been recognized that they too possess powerful
means of fighting infections, such as the ability to phagocytose
bacteria and encapsulate parasites. In addition, insects can
mount a humoral response against intruders. This is characterized by the secretion of antimicrobial peptides (AMPs) into
the hemolymph. This aspect was analyzed carefully first by
Boman et al. (1), who eventually isolated the first AMPs from
the silkmoth Hyalophora cecropia (2–4). The cloning of more
AMPs from Drosophila and other insect models revealed conserved binding sites for NF-kB proteins in their promoter
regions. This suggested that the mechanisms that induce AMP
production in response to infection might be evolutionarily
conserved (5–7). In addition to its function in development,
the dorsal gene, coding for an NF-kB transcription factor, was
discovered to mediate immune responses in adult flies, together
with another NF-kB protein-coding gene, DIF, and an additional set of genes, including Toll, tube, and pelle, belonging to
the Toll signaling pathway (8–13, reviewed in Ref. 14). Subsequently, genes coding for TLRs also were found in the human
genome. The discovery of these pattern recognition receptors
highlighted similarities between the human and Drosophila innate immune systems (15–18). However, the Toll pathway only
*Laboratory of Experimental Immunology, BioMediTech, University of Tampere, FIN33014 Tampere, Finland; †Department of Pediatrics, Tampere University Hospital,
FIN-33521 Tampere, Finland; ‡Department of Pediatrics, Medical Research Center
Oulu, University of Oulu, FIN-90014 Oulu, Finland; and xDepartment of Children
and Adolescents, Oulu University Hospital, FIN-90029 Oulu, Finland
Received for publication December 10, 2013. Accepted for publication February 11,
2014.
Address correspondence and reprint requests to Prof. Mika Rämet, University of Tampere,
FIN-33014 Tampere, Finland. E-mail address: [email protected]
www.jimmunol.org/cgi/doi/10.4049/jimmunol.1303309
controls the expression of a limited set of immune response genes
in Drosophila. The immune deficiency (Imd) pathway, which
regulates the activity of a third Drosophila NF-kB protein called
Relish (19), controls the expression of most of the Drosophila
AMPs and, thus, is indispensable for normal immunity (20).
Peptidoglycan-recognition proteins and activation of the Imd pathway
Microbial recognition is the first step in initiating the immune
response via the Imd signaling pathway. For pathogen detection, the innate immune system uses specific, genomeencoded pattern recognition molecules that bind conserved
structures, which are found on pathogens but are absent in the
host (21). Peptidoglycan (PGN) is a good example of such
a structure: it is present on most bacteria and is composed of
conserved polymers of b-1,4-linked N-acetylglucosamine and
N-acetylmuramic acid cross-linked by short stem peptides,
which vary between different types of bacteria. PGN is recognized and bound by conserved host proteins, called PGNrecognition proteins (PGRPs), which share a 160-aa PGRP
domain. Mammals have a family of four PGRPs, whereas
insects have more (e.g., 13 genes coding for 19 proteins in
Drosophila) (22, 23). The mammalian PGRPs are secreted
proteins that bind bacterial muramyl peptides. Some mammalian PGRPs have an amidase activity, probably to eliminate
the proinflammatory PGN, whereas others are more diverged
from the insect genes and function directly as bactericidal
proteins (24–26). It appears that mammalian PGRPs do not
possess signaling activity.
Insect PGRPs can act both as enzyme-active amidases that
degrade PGN and activate signal-transduction pathways and
proteolytic cascades (Fig. 1). Insect PGRPs are classified as
short (S) or long (L), according to their transcript size: short
PGRPs have signal peptides and can be extracellular proteins,
whereas long PGRPs can be intracellular, extracellular, and
transmembrane proteins. Of the Drosophila PGRPs, PGRPSA and PGRP-SD are needed for activating the Toll pathway
(14, 27, 28). No immunological in vivo phenotype has been
demonstrated for the amidases PGRP-SB1 and PGRP-SB2,
even though PGRP-SB1 is strongly induced postinfection,
and its bactericidal activity is shown in vitro (29–31). The
function of PGRP-LD is unclear. The other PGRPs either
positively or negatively regulate the Imd pathway.
Abbreviations used in this article: AMP, antimicrobial peptide; Iap2, inhibitor of apoptosis 2; IKK, IkB kinase; Imd, immune deficiency; PGN, peptidoglycan; PGRP,
peptidoglycan-recognition protein, TCT, tracheal cytotoxin.
Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00
Downloaded from http://www.jimmunol.org/ by guest on June 18, 2017
The fruit fly, Drosophila melanogaster, has helped us to
understand how innate immunity is activated. In addition to the Toll receptor and the Toll signaling pathway, the Drosophila immune response is regulated by
another evolutionarily conserved signaling cascade, the
immune deficiency (Imd) pathway, which activates NFkB. In fact, the Imd pathway controls the expression of
most of the antimicrobial peptides in Drosophila; thus,
it is indispensable for normal immunity in flies. In this
article, we review the current literature on the Drosophila
Imd pathway, with special emphasis on its role in the
(patho)physiology of different organs. We discuss the systemic response, as well as local responses, in the epithelial
and mucosal surfaces and the nervous system. The
Journal of Immunology, 2014, 192: 3455–3462.
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BRIEF REVIEWS: THE DROSOPHILA Imd SIGNALING PATHWAY
Regulation of the Imd signaling pathway
FIGURE 1. The Drosophila PGRPs and their roles in immunity. References
are shown in parentheses. Lys-type PGN, lysine-type PGN.
PGRP-LC is a transmembrane receptor that preferably
binds a meso-diaminopimelic acid–type PGN found on Gramnegative bacteria and certain Gram-positive bacteria, such as
Bacillus spp. (32, 33). It functions as the principal receptor for
mediating the activation of the Imd pathway in a systemic
infection and locally in the most anterior part of the midgut
(34–37). PGRP-LC is spliced into several isoforms, three of
which have been characterized. PGRP-LCx recognizes polymeric PGN; PGRP-LCa does not directly bind PGN, but it
acts as a coreceptor with PGRP-LCx to bind monomeric
PGN fragments called tracheal cytotoxin (TCT) (32, 38, 39).
PGRP-LC mutant flies are still responsive toward TCT. This
is due to PGRP-LE, which is found in two forms (40, 41). The
short form is secreted and binds PGN in the hemolymph (42)
and is thought to assist Imd signaling by presenting PGN to
PGRP-LC, although the export mechanism of PGRP-LE has
not been characterized. The full-length PGRP-LE remains in
the cytoplasm, where it is thought to recognize TCT fragments that gain access to the cell. Binding of TCT leads to the
oligomerization of cytoplasmic PGRP-LE in a head-to-tail
fashion (39). Ectopic expression of PGRP-LE in the fat body
The Drosophila Imd pathway is often compared with TNFR
signaling in mammals, although the Imd pathway also shares
similarities with the TLR signaling pathways. The Imd and
TNFR signaling pathways are shown schematically in Fig. 2,
with the conserved signaling molecules indicated by similar
shapes and colors. In essence, activation of the Imd pathway
and TNF-a target genes require activation of the transcription
factor Relish and NF-kB, respectively (19). In mammalian
NF-kB signaling, activation of the transcription factor is
achieved by phosphorylation of the inhibitor protein IkB by
the IkB kinase (IKK) complex. The phosphorylated IkB is
degraded, and NF-kB is released.
FIGURE 2. Schematic representation of the Drosophila Imd pathway and
human TNFR signaling. Conserved components are indicated by similar
shapes and colors. bend, bendless; eff, effete; Key, Kenny; K63 Ub, K63
polyubiquitination; NEMO, NF-kB essential modulator; TAB, TAK1-binding
protein; TRADD, TNFR1-associated death domain.
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is sufficient to activate AMP expression, in a cell-autonomous
fashion, in the absence of infection. It also was shown that cytoplasmic PGRP-LE can activate the Imd pathway, independently of PGRP-LC, by interacting with Imd (40–43). PGRPLE is the only intracellular pathogen receptor identified in Drosophila. The intracellular form is able to activate autophagy,
whereas the transmembrane form can activate a prophenoloxidase cascade together with PGRP-LC (42, 44, 45).
PGRP-LF is a transmembrane protein that resembles PGRPLC but lacks the intracellular signaling domain and does not
bind PGN. PGRP-LF acts as an inhibitor of Imd signaling by
binding PGRP-LC and preventing its dimerization (46–48).
PGRP-LA is also predicted not to bind PGN and recently was
shown to be dispensable for systemic infections. However,
consistent with its expression profile, PGRP-LA appears to
positively regulate the Imd pathway in barrier epithelia, such
as the trachea and the gut (49). PGRP-LB, PGRP-SC1A,
PGRP-SC1B, and PGRP-SC2 have an amidase activity and
are shown to play somewhat redundant roles in downregulating the Imd pathway during a systemic response.
PGRP-LB is the major regulator in the gut. The amidase
PGRPs digest PGN into short, nonimmunogenic or less immunogenic fragments and, therefore, prevent or reduce the
activation of defense mechanisms (30, 31).
The Journal of Immunology
proteins, Ird5 and Kenny, are associated with SUMO proteins, but only Ird5 is sumoylated on a conserved site, K152,
which is needed for the activation of the Imd pathway (82). A
proteomics analysis described in the same study identified 102
gene products that interacted with the core Imd pathway
components and affected the activity of several reporter genes
in response to a Gram-negative bacterial challenge in RNA
interference assays. These gene products included a number
of histone acetyltransferases and components of chromatinremodeling complexes, such as the SWI/SNF complex. These
discoveries indicate that the regulation of the Imd pathway
involves DNA modifications (82). The Imd pathway is also
positively regulated by a nuclear protein called Akirin (83). A
recent study showed that, during myogenesis, Akirin colocalizes and genetically interacts with subunits of the SWI/SNFclass chromatin-remodeling complex to optimize gene expression by the transcription factor Twist. It remains to be
studied whether Akirin provides a similar link between transcription factors and the chromatin-remodeling machinery in
Imd signaling (84). Akirin shows high conservation in both
sequence and function, and in addition to Drosophila, it was
found to positively regulate NF-kB signaling in other insects,
mammals, and reptiles (83). Akirin may even provide a target
Ag for the development of a vaccine against insect vectorborne diseases (e.g., Ref. 85).
Moreover, the activity of the Imd pathway is negatively regulated at the transcriptional level by the transcription factors
zfh1 and the AP-1/Stat92E complex. Zfh1 strongly downregulates the Imd pathway activity in vitro, but its role in vivo
is more difficult to study because of developmental effects
(83, 86–88). The JNK pathway transcription factor AP-1,
the Stat92E transcription factor, and Dsp1 can form a complex
that binds to the promoters of Relish target genes. Complex
formation leads to recruitment of the histone deacetylase
dHDAC1, the replacement of Relish, and target gene downregulation, indicating that cross-talk between the Drosophila
immune signaling pathways is needed for proper regulation of
these genes (86, 87).
One of the target genes of the mammalian NF-kB protein is
its own inhibitor, IkB. This creates a negative feedback loop,
which is a major regulatory mechanism for the signaling
pathways (89). Because Relish itself contains IkB, this method
of regulation is not feasible in Drosophila. Instead, the Imd
pathway is subject to other negative feedback mechanisms,
such as the rapid induction of a gene called pirk (90, 91). Pirk
expression appears to be induced by the Ras/MAPK pathway
as well, suggesting that Ras/MAPK signaling functions in
immunity by negatively regulating the Imd pathway (92).
Pirk interacts with the receptors PGRP-LC and PCRP-LE
and the adaptor protein Imd, thus likely interrupting signal
transduction at the receptor complex (91, 93, 94).
20-Hydroxyecdysterone (ecdysone) is a steroid hormone
known to coordinate tissue remodeling in flies undergoing
metamorphosis, including the phagocytosis of dead cells. In
addition, it is needed for the optimal phagocytic activity of
hemocytes in response to bacteria (95). Ecdysone also was
reported to regulate the activity of the Imd pathway in adult
flies via its target genes, whose products are needed for
PGRP-LC expression. In addition, some of these proteins
appear to directly regulate the expression of a subset of the
Imd pathway target genes (96).
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However, like in the mammalian Rel proteins p100 and
p105, IkB is contained in the C terminus of Relish. This is
thought to mask the nuclear localization signal in the N terminus and inhibit Relish dimerization by the Rel homology
domain. Therefore, in addition to phosphorylation, the activation of Relish requires cleavage of the inhibitory C-terminal
part. This is likely accomplished by the caspase Dredd, because it was shown to cleave Relish in vitro (50).
Binding of PGN to the receptor results in recruitment of
a signaling complex consisting of Imd, a death domain protein homologous to mammalian RIP1, the adaptor protein
dFadd, and the caspase-8 homolog Dredd (20, 51–53). Dredd
becomes activated by ubiquitination by the E3-ligase inhibitor of apoptosis 2 (Iap2) (54), which associates with the E2ubiquitin–conjugating enzymes UEV1a, Bendless (Ubc13),
and Effete (Ubc5) (55). Once activated, Dredd cleaves Imd,
removing a 30-aa N-terminal fragment, and creates a novel
binding site for Iap2, which can then K63-ubiquitinate Imd
(54, 56). This leads to the recruitment and activation of the
Tab2/Tak1 complex, which is responsible for the phosphorylation and activation of the Drosophila IKK complex (57–
60). Relish is activated by the phosphorylation of multiple
sites at its N terminus by the IKK complex (59). It was shown
that phosphorylation of serine residues S528 and S529 is
required for efficient recruitment of RNA polymerase II to
the promoters of Relish target genes (59, 61). The C-terminal
part (Rel-49) remains in the cytoplasm, and the active
N-terminal part (Rel-68) translocates into the nucleus to activate the transcription of genes coding for AMPs, such as
Diptericin and Cecropin (50, 62). Like in mammalian TNFR
signaling, the Drosophila Imd pathway bifurcates into the JNK
pathway at the level of Tak1 and Tab2 (63–65).
The activity of Imd signaling is fine-tuned at multiple levels
by several molecules and mechanisms (66–68). For example,
the ubiquitination state of various pathway components is
delicately regulated. The E3-ligase Iap2 has been identified in
many large-scale screens for Imd pathway regulators (60, 66,
69, 70), and it also was shown to be essential for Imd pathway–mediated AMP expression and bacterial resistance in
vivo (60, 65, 71). In addition, a number of ubiquitinating and
deubiquitinating enzymes have been implicated in the negative regulation of the signaling pathway. The ubiquitin-specific
protease dUSP36/Scny prevents the accumulation of the activated, K63-ubiquitinated Imd and promotes its K48-linked
ubiquitination and subsequent degradation (72). faf is a deubiquitinating enzyme that also was proposed to regulate the
ubiquitination state of Imd (73). Tak1 is targeted for ubiquitination and degradation by the RING-finger protein
POSH (74). CYLD is a deubiquitinating enzyme that downregulates mammalian TNFR signaling by inactivating TRAF2.
Drosophila CYLD interacts with the IKK protein Kenny and
also negatively regulates Imd signaling (75, 76). Activated
Relish is targeted for ubiquitination and proteasomal degradation by the SCF complex (77), possibly promoted by the
ubiquitin-binding protein dRYBP (78). Dredd is inhibited by
the RING-domain containing protein Dnr1 (79, 80), whereas
Caspar, a homolog of the mammalian FAF1, inhibits the
Dredd-mediated cleavage of Relish (81).
In addition to ubiquitination, another posttranscriptional
modification that regulates signaling molecules is the addition
of SUMO. Recently, it was shown that both Drosophila IKK
3457
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BRIEF REVIEWS: THE DROSOPHILA Imd SIGNALING PATHWAY
The role of Imd-pathway activation in systemic and epithelial immunity
In addition to initiating the systemic response in the fat body,
the Imd pathway is activated locally in several tissues (Fig. 3).
Inducible immune responses in the epithelial and mucosal
surfaces, such as the Drosophila tracheal airway system and
the digestive system, are important, because these surfaces are
constantly exposed to potentially pathogenic bacteria, fungi,
and yeast (97, 98). In the trachea, an infection triggers the
Imd pathway–mediated reactivation of a set of tracheal development genes, a survival reaction that remodels the epithelial tissue damaged upon infection (99). Also, AMPs are
induced, and their expression is antagonized via a signaling
route involving a Toll family member Toll-8/Tollo (100).
Salivary glands have the potential to contribute to intestinal
immunity by secreting soluble proteins and peptides into the
saliva that rinses through the digestive system (101). Importantly, there are marked differences in the sets of genes induced in different tissues. For example, a microarray study
comparing the immune response in the fat body, gut, and
trachea showed that there is only a small set of “universal”
Imd pathway target genes, mainly consisting of AMPs and
pathway components; the rest of the infection-inducible genes
are more tissue specific (49). Also, Imd pathway–mediated
AMPs were shown to activate specific responses in the nervous
system (e.g., Ref. 102).
The gut microbial community, or microbiome, is now recognized as an integral part of the host system with important
metabolic activities (103). The Drosophila gut microbiome is
a dynamic structure: its composition varies widely within and
among Drosophila populations and species (104), and it is
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FIGURE 3. Schematic representation of tissue-specific (dys)functions and the regulation of the Imd pathway. In Drosophila, systemic AMP expression is induced
in the fatbody cells by PGRP-LC–mediated recognition of PGN fragments and monomers (TCT) and leads to the secretion of AMPs into the hemolymph. In the
gut, the negative regulators Pirk, Caudal, PGRP-LB, and PGRP-LF maintain tissue homeostasis by preventing extensive Imd pathway activation by commensal
microbes. In contrast, pathogenic bacteria are thought to secrete more PGN and, therefore, activate Imd pathway–mediated AMP expression. TCT molecules that
cross the epithelial barrier and gain access to the hemolymph can also elicit a systemic response in the fatbody. PGRP-LA and Tollo regulate Imd pathway activity,
specifically in the trachea (airway epithelium). In the brain, Dredd is activated independently of the upstream pathway components, and Relish-mediated AMP
expression leads to neurodegeneration. Cad, Caudal; ECT4, ectoderm-expressed 4; Spz2, Spaetzle 2.
The Journal of Immunology
The Imd pathway in immune senescence and neurodegeneration
In humans, aging is associated with changes in immunity, such
as upregulation of the innate immune system. This can lead to
chronic inflammation, with immune functions actually deteriorating, making the elderly more susceptible to infections
(114). In Drosophila, aging is also characterized by the increased expression of immune-related genes, including several
antimicrobial peptides, PGRPs, and Relish (115–117), increased bacterial loads (118), and more persistent AMP activation upon infection (119). This suggests that flies might develop a chronic inflammation-like condition resembling that
seen in humans. Genetic studies show that overexpression of
PGRP-LE or PGRP-LC in the fat body activates the Imd
pathway, which enhances the flies’ resistance against pathogens and has no acute effects on reproduction or general fitness. However, long-term activation of the Imd pathway creates
an inflammation-like state and results in reduced lifespan,
suggesting that maintaining an active immunity is physiologically costly in the long run (114, 120). Evidence supporting this hypothesis includes a delay in the age-related
immune activation in flies reared on a calorie-restricted diet
(116). Moreover, Relish mutant flies live longer than do wildtype flies on a calorie-restricted diet (121), and female Relish
and Imd mutants do not show signs of reduced fecundity
(number of eggs laid) after injection with killed bacteria
(119). Thus, the Imd pathway appears to be involved in
mediating chronic inflammation and immune senescence, but
the exact mechanisms need to be studied further.
Many human age-related neurodegenerative diseases also
are characterized by the activation of inflammatory pathways
in neural cells, caused by the accumulation of aberrant protein aggregates, such as the b-amyloid fibrils in Alzheimer’s
disease. Therefore, an elevation in TNF-a levels and NF-kB
activity are often found to contribute to the disease pathology
by inducing the expression of additional proinflammatory
molecules or cell death (122). Similarly, involvement of the
Toll or Imd pathways in neurodegeneration has been observed in Drosophila. An experimental bacterial infection in
the brain causes progressive, age-dependent neurodegeneration
at the injection site, together with locomotive defects. The
phenotype is dependent on Relish, and strikingly, overexpression of individual AMPs alone in neurons or glial cells
is sufficient to cause these symptoms. This suggests that
AMPs could be directly cytotoxic to brain cells (123). Drosophila neurodegeneration disease models also have been used
to study immune-related diseases in the nervous system.
Ataxia-telangiectasia is a rare disease caused by a recessive
mutation of the ATM gene, which encodes a DNA damageresponsive protein kinase. In Drosophila, a temperaturesensitive allele of ATM or the expression of an ATM RNA
interference construct in glial cells leads to reduced longevity
and mobility, increased death of neurons and glial cells, and
increased expression of immune-response genes (124). These
changes are dependent on Relish but not Dif or Imd (102).
Furthermore, Dredd has been associated with retinal degeneration caused by a mutation in an eye-specific phospholipase
C (norpA). In this model, the light-dependent endocytosis of
rhodopsin, its accumulation in the late endosomes, and the
resulting death of photoreceptor cells are not dependent on
the developmental apoptosis machinery but require Dredd.
Moreover, this retinal phenotype was rescued by mutations in
Relish and key, but not Imd or Fadd, suggesting an alternative
means for Dredd regulation. In addition, overexpression of
active Relish during development has detrimental effects on
various tissues and cell types, such as neurons, photoreceptor
and eye cells, and the wing (125). Thus, several Drosophila
models demonstrate the activation of Relish and its target
genes in neurodegeneration. The neurotoxicity is dependent
on Dredd but not the upstream Imd pathway components,
and aberrant Dredd activation due to a mutation in the negative regulator Dnr1 is also sufficient to cause neurotoxicity
(102, 123, 125).
The importance of the Toll pathway in Drosophila development is well established, and accumulating evidence suggests that the Imd pathway also has functions distinct from
its conventional roles. Therefore, Drosophila appears to be an
advantageous model for studying the role of innate immunity
signaling pathways and inflammatory responses in various
contexts, such as aging, and the function and dysfunction of
the nervous system.
Conclusions
The research on Drosophila immunity has blossomed during
the past 20 years. The Imd signaling pathway has been at the
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influenced by bacteria introduced into the gut by ingestion
(105). The microbial community needs to balance a tolerance
toward commensal bacteria and alertness toward pathogenic
invasion, as well as the homeostasis between gut microbes and
the host. There are two parallel systems in Drosophila that
control this host–microbe homeostasis: the DUOX pathway(s)
(106) and the Imd pathway. The Imd pathway is activated
upon PGN binding by PGRP-LC and, specifically in the gut,
by PGRP-LE (41, 107). Evidently, mechanisms for controlling the immune response play a major role in maintaining
homeostasis. The first checkpoint is PGN sensing: pathogens
that divide more rapidly than commensals shed more PGN
upon cell division and, therefore, get recognized by the Imd
pathway, unlike commensals (reviewed in Ref. 108). The
second control mechanism is the expression of negative regulators that downregulate the Imd pathway at all of its levels.
Amidase PGRPs (Fig. 1), especially PGRP-LB (30, 37), degrade and scavenge PGN in the gut lumen to prevent it from
crossing the gut barrier. However, in some pathogenic infections, PGN fragments may translocate across the gut epithelium and trigger a systemic response (37, 109, 110) (Fig. 3).
Some negative regulators directly bind components of the Imd
pathway: PGRP-LF dimerizes with a PGRP-LCx isoform to
form a competitive nonsignaling complex (46, 47). Pirk, which
interacts with the receptor and Imd, is needed for normal
immune tolerance in the gut (94). Furthermore, it was proposed recently that the transglutaminase protein inhibits Relish
activity by catalyzing the polymerization of N-terminal Relish
molecules (111). Another level of control in the immune system includes Caudal, the intestinal homeobox gene (112),
which is expressed in a defined compartment in the adult fly
midgut (113). Silencing of Caudal constitutively activates
AMPs and leads to intestinal disorders, compromising the fitness of the animal (112, 113). Caudal, together with other gutspecific transcription factors, has important functions in patterning the expression of AMPs and other intestinal genes
(113).
3459
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BRIEF REVIEWS: THE DROSOPHILA Imd SIGNALING PATHWAY
center of this investigation. Today, the genes that are required
for the systemic Imd pathway–mediated AMP response are
relatively well known, and the understanding of their respective molecular mechanisms is constantly improving. How
the Imd response is tuned (down) is still under active investigation, and studies may give clues to understanding the
(mis)regulation of mammalian NF-kB activity. The gut immune response is arguably the most studied aspect of the
Drosophila immune response. Comprehending the mechanisms that regulate the Imd pathway in this context can be
expected to lead to discoveries related to chronic inflammatory diseases of the gastrointestinal tract. The importance of
the Imd pathway in neurodegeneration is emerging, leading
to increased research on the pathway in this context. For
example, the trigger for the neurotoxic activation of Relish is
yet to be found.
Acknowledgments
Disclosures
The authors have no financial conflicts of interest.
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