Necrosis-Driven Systemic Immune Response Alters SAM Metabolism through the FOXO-GNMT Axis

Fumiaki Obata, Erina Kuranaga, Katsura Tomioka, Ming Ming, Asuka Takeishi, Chun Hong Chen, Tomoyoshi Soga, Masayuki Miura

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Abstract

Sterile inflammation triggered by endogenous factors is thought to contribute to the pathogenesis of acute and chronic inflammatory diseases. Here, we demonstrate that apoptosis-deficient mutants spontaneously develop a necrosis-driven systemic immune response in Drosophila and provide an in vivo model for studying the organismal response to sterile inflammation. Metabolomic analysis of hemolymph from apoptosis-deficient mutants revealed increased sarcosine and reduced S-adenosyl-methionine (SAM) levels due to glycine N-methyltransferase (Gnmt) upregulation. We showed that Gnmt was elevated in response to Toll activation induced by the local necrosis of wing epidermal cells. Necrosis-driven inflammatory conditions induced dFoxO hyperactivation, leading to an energy-wasting phenotype. Gnmt was cell-autonomously upregulated by dFoxO in the fat body as a possible rheostat for controlling energy loss, which functioned during fasting as well as inflammatory conditions. We propose that the dFoxO-Gnmt axis is essential for the maintenance of organismal SAM metabolism and energy homeostasis.

Original languageEnglish
Pages (from-to)821-833
Number of pages13
JournalCell Reports
Volume7
Issue number3
DOIs
Publication statusPublished - 2014 Jan 1

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Obata, F., Kuranaga, E., Tomioka, K., Ming, M., Takeishi, A., Chen, C. H., Soga, T., & Miura, M. (2014). Necrosis-Driven Systemic Immune Response Alters SAM Metabolism through the FOXO-GNMT Axis. Cell Reports, 7(3), 821-833. https://doi.org/10.1016/j.celrep.2014.03.046