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.
authors.affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Obata
authors.affiliation: Laboratory for Histogenetic Dynamics, RIKEN CDB, Kobe 650-0047, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Kuranaga
authors.affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Katsura
authors.initials: K
authors.lastname: Tomioka
authors.affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Ming
authors.initials: M
authors.lastname: Ming
authors.affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Takeishi
authors.affiliation: National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan.
authors.forename: Tomoyoshi
authors.initials: T
authors.lastname: Soga
authors.affiliation: Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan. Electronic address: miura@mol.f.u-tokyo.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miura
mesh_terms: D000818:Animals; D017209:Apoptosis; D019175:DNA Methylation; D004330:Drosophila / Q000378:metabolism; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D050938:Glycine N-Methyltransferase / Q000378:metabolism*; D007107:Immune System / Q000378:metabolism*; D055442:Metabolome; D009336:Necrosis; D010641:Phenotype; D012436:S-Adenosylmethionine / Q000378:metabolism*; D012521:Sarcosine / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; C400550:dark protein, Drosophila; D012436:S-Adenosylmethionine; D050938:Glycine N-Methyltransferase; D012521:Sarcosine