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

doi:10.1016/j.celrep.2014.03.046

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

Faculty of Environment and Information Studies

Research output: Contribution to journal › Article

32 Citations (Scopus)

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 language	English
Pages (from-to)	821-833
Number of pages	13
Journal	Cell Reports
Volume	7
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2014.03.046
Publication status	Published - 2014 Jan 1

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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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

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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.",

author = "Fumiaki Obata and Erina Kuranaga and Katsura Tomioka and Ming Ming and Asuka Takeishi and Chen, {Chun Hong} and Tomoyoshi Soga and Masayuki Miura",

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AU - Ming, Ming

AU - Takeishi, Asuka

AU - Chen, Chun Hong

AU - Soga, Tomoyoshi

AU - Miura, Masayuki

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N2 - 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.

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