Abstract
Signalling networks that control the life or death of a cell are of central interest in modern biology. While the defined roles of the c-Jun N-terminal kinase (JNK) pathway in regulating cell death have been well-established, additional factors that modulate JNK-mediated cell death have yet to be fully elucidated. To identify novel regulators of JNK-dependent cell death, we performed a dominant-modifier screen in Drosophila and found that the Toll pathway participates in JNK-mediated cell death. Loss of Toll signalling suppresses ectopically and physiologically activated JNK signalling-induced cell death. Our epistasis analysis suggests that the Toll pathway acts as a downstream modulator for JNK-dependent cell death. In addition, gain of JNK signalling results in Toll pathway activation, revealed by stimulated transcription of Drosomycin (Drs) and increased cytoplasm-to-nucleus translocation of Dorsal. Furthermore, the Spätzle (Spz) family ligands for the Toll receptor are transcriptionally upregulated by activated JNK signalling in a non-cell-autonomous manner, providing a molecular mechanism for JNK-induced Toll pathway activation. Finally, gain of Toll signalling exacerbates JNK-mediated cell death and promotes cell death independent of caspases. Thus, we have identified another important function for the evolutionarily conserved Toll pathway, in addition to its well-studied roles in embryonic dorso-ventral patterning and innate immunity.
Highlights
The excellent work for studying the pivotal functions of the Toll/IL-1R pathway in innate immunity in Drosophila and mammals earned Jules A
Ectopic expression of Egr in Drosophila eyes driven by GMRGAL4 leads to vastly reduced adult eye size [29,30], resulting from extensive cell death posterior to the morphogenetic furrow (MF) in third-instar eye discs, visualized by acridine orange (AO) staining that detects dying cells [51]
To identify additional regulators of Egr-triggered cell death, we performed a genetic screen for dominant modifiers of the GMR.Egr small-eye phenotype using the Bloomington Drosophila Stock Center Deficiency kit that covers more than 95% of the genome
Summary
The excellent work for studying the pivotal functions of the Toll/IL-1R pathway in innate immunity in Drosophila and mammals earned Jules A. Other components of the Toll pathway, including Spatzle, Tube, Pelle, Cactus and Dorsal, were characterized as crucial regulators of dorsal–ventral patterning [3,4,5,6,7,8,9]. To activate the Toll pathway in development or immunity, the first step is to cleave the inactive precursor of the Toll receptor ligand Spatzle (Spz) [8,9]. Activation of Pelle triggers the phosphorylation and degradation of Drosophila IkB factor Cactus, which sequesters Dorsal and Dif (Dorsal-related immunity factor), the NF-kB factors in Drosophila, in the cytoplasm [16]. Once Cactus is degraded in response to the signal, Dorsal and Dif translocate to the nucleus and activate the
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