title: Toll pathway modulates TNF-induced JNK-dependent cell death in Drosophila.
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.
authors.affiliation: Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, People's Republic of China.
authors.forename: Chenxi
authors.initials: C
authors.lastname: Wu
authors.affiliation: Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, People's Republic of China.
authors.forename: Changyan
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Life Sciences, Tsinghua University, Medical Science Building, D224, Beijing 100084, People's Republic of China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Dai
authors.affiliation: School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, People's Republic of China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, People's Republic of China.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, People's Republic of China.
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Li
authors.affiliation: School of Life Sciences, Tsinghua University, Medical Science Building, D224, Beijing 100084, People's Republic of China.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Pastor-Pareja
authors.affiliation: Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, 1239 Siping Road, Shanghai 200092, People's Republic of China lei.xue@tongji.edu.cn.
authors.forename: Lei
authors.initials: L
authors.lastname: Xue
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D054910:Compound Eye, Arthropod / Q000166:cytology / Q000254:growth & development; D004330:Drosophila / Q000166:cytology / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020935:MAP Kinase Signaling System; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism* / Q000502:physiology; D014921:Wings, Animal / Q000166:cytology / Q000254:growth & development
chemical_list: D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; C068721:Tl protein, Drosophila; D051193:Toll-Like Receptors; C086179:spz protein, Drosophila
keywords: Drosophila; Eiger; Toll; c-Jun N-terminal kinase; cell death