Regulation and function of cell death signaling in development, growth, and aging

Cell death in adult tissue homeostasis

Cell death occurs not only in developmental stage but also is observed in adult. In human, more than 2 x 1011 cells are thought to be replaced everyday. That consists about 0.5% of total cells in our body. Mutual communication of cell death and proliferation could be essential for tissue and body homeostasis and disorder of this interaction could underlie in many diseases. When apoptosis is prevented during Drosophila development, damage-associated molecular pattern (DAMPs) is released into the body fluid and activates Toll pathway through the cascade of Clip-domain serine protease Persephone/Spatzle pathogen sensors.
When apoptosis is inhibited in adult wing after eclosion, pro-inflammatory necrotic dell death occurred and systemic innate immune reaction was induced in this model. This inflammatory reaction leads to the energy wasting and altered SAM metabolism due to hyper activation of dFoxO in the fat body. These phenotypes indicate that the organisms systemically react and change their energy metabolism and methylation capacity in response to the local necrotic cells. Regulation of systemic energy metabolism by local necrotic cells may be direct cause or the factors of deterioration of some inflammatory diseases including cancer or diabetes and thus could be the novel therapeutic target.
Effective defense responses against infection, tissue damage and stress involve the entire organismal reactions. To maintain body homeostasis after tissue damage, a systemic wound response is induced, in which the response of each tissue is tightly orchestrated to avoid incomplete recovery or an excessive, damaging response. We provided evidence that in the systemic response to wounding by cuticle pricking, an apoptotic caspase pathway is activated
via reactive oxygen species (ROS) in the enterocytes (ECs) of midgut, cells distant to the wound site in Drosophila. We showed that a caspase-pathway mutant (dapaf-1/dark/HAC-1) has defects in homeostatic gut-cell renewal. Inhibition of caspase in fly ECs results in the production of systemic lethal factors after wounding. Our study indicated that wounding remotely controls caspase activity in gut ECs to dampen the dangerous systemic wound reaction.


Obata, F. & Miura, M. : Enhancing S-adenosyl-methionine catabolism extends Drosophila lifespan. Nat. Commun. 6:8332, 2015, doi: 10.1038/ncomms9332

Katsuyama, T., Comoglio, F., Seimiya, M., Cabuy, E., and Paro, R.: During Drosophila disc regeneration, JAK/STAT coordinates cell proliferation with Dilp8-mediated developmental delay. Proc. Natl. Acad. Sci. U S A. 112: E2327-36, 2015. doi: 10.1073/pnas.1423074112.

Obata, F., Kuranaga, E., Tomioka, K., Ming, M., Takeishi, A., Chen, C-H., Soga, T., and Miura, M.: Necrosis-driven systemic immune response alters SAM metabolism through the FOXO-GNMT axis. Cell Rep. 7, 821-833, 2014
Ming, M., Obata, F., Kuranaga, E., and Miura, M.: Persephone/Spӓtzle pathogen sensors mediate the activation of Toll receptor signaling in response to endogenous danger signals in apoptosis-deficient
Drosophila. J. Biol. Chem. 289, 7558-7568, 2014
Takeishi, A., Kuranaga, E., Tonoki, A., Misaki, K., Yonemura, S., Kanuka, H., and Miura, M.: Homeostatic epithelial renewal in the gut is required to dampen a fatal systemic wound response in Drosophila. Cell Rep. 3, 919-930, 2013

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