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 › peer-review

33 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

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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@article{1828ec825b5c4dd39e7f6bb46f690fa6,

title = "Necrosis-Driven Systemic Immune Response Alters SAM Metabolism through the FOXO-GNMT Axis",

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",

note = "Funding Information: We are grateful to Y. Imai (Musashino University) for advice on the UPLC analysis. We thank Y. Imai (Juntendo University), T. Nishimura, A. Gould, P. Leopold, S. Pletcher, G. Rubin, L. Patridge, A. Bergmann, D.J. Pan, S. Kurata, B. Lemaitre, J.L. Imler, J.M. Abrams, C. Thummel, E. Hafen, N. Perrimon, B. Edgar, the Vienna Drosophila RNAi Center, and the Bloomington Drosophila Stock Center for Drosophila stocks and antibodies. We thank T. Chihara, Y. Yamaguchi, L. Zhang, S. Kashio, T. Yamazaki, K. Takeuchi, S. Haraguchi, K. Takenaga, M. Sasaki, A. Isomura, A. Tsukioka, and Y. Fujioka for technical assistance and discussions. This work was supported by grants from the Japanese Ministry of Education, Science, Sports, Culture, and Technology (to M. Miura and E.K.) and the Uehara Memorial Foundation (to E.K.). F.O. and A.T. are research fellows of the Japan Society for the Promotion of Science. ",

year = "2014",

doi = "10.1016/j.celrep.2014.03.046",

language = "English",

volume = "7",

pages = "821--833",

journal = "Cell Reports",

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T1 - Necrosis-Driven Systemic Immune Response Alters SAM Metabolism through the FOXO-GNMT Axis

AU - Obata, Fumiaki

AU - Kuranaga, Erina

AU - Tomioka, Katsura

AU - Ming, Ming

AU - Takeishi, Asuka

AU - Chen, Chun Hong

AU - Soga, Tomoyoshi

AU - Miura, Masayuki

N1 - Funding Information: We are grateful to Y. Imai (Musashino University) for advice on the UPLC analysis. We thank Y. Imai (Juntendo University), T. Nishimura, A. Gould, P. Leopold, S. Pletcher, G. Rubin, L. Patridge, A. Bergmann, D.J. Pan, S. Kurata, B. Lemaitre, J.L. Imler, J.M. Abrams, C. Thummel, E. Hafen, N. Perrimon, B. Edgar, the Vienna Drosophila RNAi Center, and the Bloomington Drosophila Stock Center for Drosophila stocks and antibodies. We thank T. Chihara, Y. Yamaguchi, L. Zhang, S. Kashio, T. Yamazaki, K. Takeuchi, S. Haraguchi, K. Takenaga, M. Sasaki, A. Isomura, A. Tsukioka, and Y. Fujioka for technical assistance and discussions. This work was supported by grants from the Japanese Ministry of Education, Science, Sports, Culture, and Technology (to M. Miura and E.K.) and the Uehara Memorial Foundation (to E.K.). F.O. and A.T. are research fellows of the Japan Society for the Promotion of Science.

PY - 2014

Y1 - 2014

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.

AB - 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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JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

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ER -

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

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