Cooperative control of Drosophila immune responses by the JNK and NF-κB signaling pathways

Delaney, Joseph R.; Stöven, Svenja; Uvell, Hanna; Anderson, Kathryn V.; Engström, Ylva; Mlodzik, Marek

doi:10.1038/sj.emboj.7601182

Cited by 163 publications

(150 citation statements)

References 64 publications

Supporting

Mentioning

137

Contrasting

Order By: Relevance

“…Our findings also demonstrate that Tak1 can induce constitutive Dpt expression above basal levels as expected, but the other chimeras and Slpr WT had no effect (Figure 8). The latter observation is consistent with the absence of immunity phenotypes of slpr mutants (not shown), the resistance of adults expressing dominant negative Slpr AAA to E.coli infection (Figure 7), and previous reports that expression of activated Hep failed to induce ectopic dpt expression without bacterial challenge (Delaney et al 2006). Thus, in the context of the Rel signaling branch, Tak1 is highly specific vs. Slpr.…”

Section: Contributions Of Nonkinase Domainssupporting

confidence: 73%

“…Intriguingly, expression of dominant negative Slpr also significantly attenuated Dpt induction. These results could be interpreted to support the contention that JNK signaling is required for optimal AMP expression Delaney et al 2006). Finally, Figure 6 The C-terminal region of Tak1 is sufficient to inhibit ectopic eiger-induced cell death.…”

Section: Differential Localization Of Chimeric Proteins In Two Tissuesupporting

confidence: 62%

“…Tak1 Ct -bearing proteins inhibited induction of Dpt at least as well as Tak1 K46R , whose expression was actually far greater based on RT-PCR amplification with Tak1 genespecific primers (Figure 8 and Figure S2). Thus, there was a partial disconnect between Dpt regulation and infection susceptibility vis-à-vis expression of the T Ct and Slpr AAA constructs, the latter of which might be due to its influence on JNK signaling, resulting in submaximal AMP induction upon infection as noted by others Delaney et al 2006). Given that innate immune signaling is highly complex and regulated at many levels to prevent unnecessary activation or prolonged response (Schneider 2007), it is perhaps not surprising that the effects on Dpt induction did not fully account for the overall systemic response.…”

Section: Contributions Of Nonkinase Domainsmentioning

confidence: 99%

See 2 more Smart Citations

Domain Specificity of MAP3K Family Members, MLK and Tak1, for JNK Signaling inDrosophila

Stronach

Lennox²,

Garlena

2014

Genetics

View full text Add to dashboard Cite

A highly diverse set of protein kinases functions as early responders in the mitogen-and stress-activated protein kinase (MAPK/SAPK) signaling pathways. For instance, humans possess 14 MAPK kinase kinases (MAP3Ks) that activate Jun kinase (JNK) signaling downstream. A major challenge is to decipher the selective and redundant functions of these upstream MAP3Ks. Taking advantage of the relative simplicity of Drosophila melanogaster as a model system, we assessed MAP3K signaling specificity in several JNK-dependent processes during development and stress response. Our approach was to generate molecular chimeras between two MAP3K family members, the mixed lineage kinase, Slpr, and the TGF-b activated kinase, Tak1, which share 32% amino acid identity across the kinase domain but otherwise differ in sequence and domain structure, and then test the contributions of various domains for protein localization, complementation of mutants, and activation of signaling. We found that overexpression of the wild-type kinases stimulated JNK signaling in alternate contexts, so cells were capable of responding to both MAP3Ks, but with distinct outcomes. Relative to wild-type, the catalytic domain swaps compensated weakly or not at all, despite having a shared substrate, the JNK kinase Hep. Tak1 C-terminal domain-containing constructs were inhibitory in Tak1 signaling contexts, including tumor necrosis factordependent cell death and innate immune signaling; however, depressing antimicrobial gene expression did not necessarily cause phenotypic susceptibility to infection. These same constructs were neutral in the context of Slpr-dependent developmental signaling, reflecting differential subcellular protein localization and by inference, point of activation. Altogether, our findings suggest that the selective deployment of a particular MAP3K can be attributed in part to its inherent sequence differences, cellular localization, and binding partner availability. P ROTEIN kinases are common transducers of information within cells. Indeed, reversible phosphorylation of substrates, by the opposing activities of kinases and phosphatases, is a major currency in cells forming the basis for information relay in many signaling pathways, ultimately transforming cell behavior in response to a changing environment. Unregulated kinase activity, however, has been implicated in numerous diseases of medical concern, notably cancer. One family in particular, the mitogen-activated protein kinases (MAPKs), composed of ERK, p38, and JNK enzymes, are central to a vast array of cellular and pathological processes

show abstract

Section: Contributions Of Nonkinase Domainssupporting

confidence: 73%

Section: Differential Localization Of Chimeric Proteins In Two Tissuesupporting

confidence: 62%

Section: Contributions Of Nonkinase Domainsmentioning

confidence: 99%

See 1 more Smart Citation

Domain Specificity of MAP3K Family Members, MLK and Tak1, for JNK Signaling inDrosophila

Stronach

Lennox²,

Garlena

2014

Genetics

View full text Add to dashboard Cite

show abstract

“…TAK1 has been proposed as a possible link that activates both the IMD and JNK pathways (36)(37)(38). However, previous work has shown no protective role of TAK1 against P. falciparum NF54 WT in A. gambiae (31).…”

Section: Resultsmentioning

confidence: 82%

Plasmodium falciparum evades mosquito immunity by disrupting JNK-mediated apoptosis of invaded midgut cells

Ramphul

Garver

Molina-Cruz

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

110

113

View full text Add to dashboard Cite

The malaria parasite, Plasmodium, must survive and develop in the mosquito vector to be successfully transmitted to a new host. The Plasmodium falciparum Pfs47 gene is critical for malaria transmission. Parasites that express Pfs47 (NF54 WT) evade mosquito immunity and survive, whereas Pfs47 knockouts (KO) are efficiently eliminated by the complement-like system. Two alternative approaches were used to investigate the mechanism of action of Pfs47 on immune evasion. First, we examined whether Pfs47 affected signal transduction pathways mediating mosquito immune responses, and show that the Jun-N-terminal kinase (JNK) pathway is a key mediator of Anopheles gambiae antiplasmodial responses to P. falciparum infection and that Pfs47 disrupts JNK signaling. Second, we used microarrays to compare the global transcriptional responses of A. gambiae midguts to infection with WT and KO parasites. The presence of Pfs47 results in broad and profound changes in gene expression in response to infection that are already evident 12 h postfeeding, but become most prominent at 26 h postfeeding, the time when ookinetes invade the mosquito midgut. Silencing of 15 differentially expressed candidate genes identified caspase-S2 as a key effector of Plasmodium elimination in parasites lacking Pfs47. We provide experimental evidence that JNK pathway regulates activation of caspases in Plasmodium-invaded midgut cells, and that caspase activation is required to trigger midgut epithelial nitration. Pfs47 alters the cell death pathway of invaded midgut cells by disrupting JNK signaling and prevents the activation of several caspases, resulting in an ineffective nitration response that makes the parasite undetectable by the mosquito complement-like system.

show abstract

“…Activation of the JNK signaling pathway is induced by pathogens (24,25) and is required for the expression of AMPs (26). Therefore, we examined whether the JNK signaling pathway is also activated in senju 1 by measuring the levels of puckered (puc) mRNA, which are increased by JNK pathway activation (27).…”

Section: Resultsmentioning

confidence: 99%

Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation

Yamamoto-Hino

Muraoka

Kondo

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The innate immune system is the first line of defense encountered by invading pathogens. Delayed and/or inadequate innate immune responses can result in failure to combat pathogens, whereas excessive and/or inappropriate responses cause runaway inflammation. Therefore, immune responses are tightly regulated from initiation to resolution and are repressed during the steady state. It is well known that glycans presented on pathogens play important roles in pathogen recognition and the interactions between host molecules and microbes; however, the function of glycans of host organisms in innate immune responses is less well known. Here, we show that innate immune quiescence and strength of the immune response are controlled by host glycosylation involving a novel UDPgalactose transporter called Senju. In senju mutants, reduced expression of galactose-containing glycans resulted in hyperactivation of the Toll signaling pathway in the absence of immune challenges. Genetic epistasis and biochemical analyses revealed that Senju regulates the Toll signaling pathway at a step that converts Toll ligand Spatzle to its active form. Interestingly, Toll activation in immune-challenged wild type (WT) flies reduced the expression of galactose-containing glycans. Suppression of the degalactosylation by senju overexpression resulted in reduced induction of Toll-dependent expression of an antimicrobial peptide, Drosomycin, and increased susceptibility to infection with Gram-positive bacteria. These data suggest that Senju-mediated galactosylation suppresses undesirable Toll signaling activation during the steady state; however, Toll activation in response to infection leads to degalactosylation, which raises the immune response to an adequate level and contributes to the prompt elimination of pathogens.innate immunity | glycosylation | Toll pathway | nucleotide sugar transporter | galactose

show abstract

Cooperative control of Drosophila immune responses by the JNK and NF-κB signaling pathways

Cited by 163 publications

References 64 publications

Domain Specificity of MAP3K Family Members, MLK and Tak1, for JNK Signaling inDrosophila

Domain Specificity of MAP3K Family Members, MLK and Tak1, for JNK Signaling inDrosophila

Plasmodium falciparum evades mosquito immunity by disrupting JNK-mediated apoptosis of invaded midgut cells

Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation

Contact Info

Product

Resources

About