Abstract
Although Jun amino-terminal kinase (JNK) is known to mediate a physiological stress signal that leads to cell death, the exact role of the JNK pathway in the mechanisms underlying intrinsic cell death is largely unknown. Here we show through a genetic screen that a mutant of Drosophila melanogaster tumour-necrosis factor receptor-associated factor 1 (DTRAF1) is a dominant suppressor of Reaper-induced cell death. We show that Reaper modulates the JNK pathway through Drosophila inhibitor-of-apoptosis protein 1 (DIAP1), which negatively regulates DTRAF1 by proteasome-mediated degradation. Reduction of JNK signals rescues the Reaper-induced small eye phenotype, and overexpression of DTRAF1 activates the Drosophila ASK1 (apoptosis signal-regulating kinase 1; a mitogen-activated protein kinase kinase kinase) and JNK pathway, thereby inducing cell death. Overexpresson of DIAP1 facilitates degradation of DTRAF1 in a ubiquitin-dependent manner and simultaneously inhibits activation of JNK. Expression of Reaper leads to a loss of DIAP1 inhibition of DTRAF1-mediated JNK activation in Drosophila cells. Taken together, our results indicate that DIAP1 may modulate cell death by regulating JNK activation through a ubiquitin–proteasome pathway.
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Acknowledgements
We thank T. Hiratou and R. Akai for technical support; H. Steller, G. M. Rubin, B. Hay, M. Nakamura, T. Adachi-Yamada and J. Nambu for fly stocks; the Berkeley Drosophila Genome Project for reagents and information; the Bloomington Stock Center for fly stocks; Y. Uchiyama for encouragement; and B. Nelson for critical reading. This work was supported in part by grants from the Japanese Ministry of Education, Science, Sports, Culture and Technology (K.S., H.O. and M. M.) and by the Core Research for Evolutional Science and Technology (H.O.), the Japan Science and Technology Corporation, and the RIKEN Bioarchitect Research Project. T.I. is a research fellow of the Japan Society for the Promotion of Science. H.K. is a research fellow of the Special Postdoctoral Researchers Program, RIKEN. E.K. is a research fellow of the Junior Research Associate Program, RIKEN.
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Kuranaga, E., Kanuka, H., Igaki, T. et al. Reaper-mediated inhibition of DIAP1-induced DTRAF1 degradation results in activation of JNK in Drosophila. Nat Cell Biol 4, 705–710 (2002). https://doi.org/10.1038/ncb842
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DOI: https://doi.org/10.1038/ncb842
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