Necrosis-driven systemic immune response alters SAM metabolism through the FOXO-GNMT axis

Cell Rep. 2014 May 8;7(3):821-33. doi: 10.1016/j.celrep.2014.03.046. Epub 2014 Apr 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • DNA Methylation
  • Drosophila / metabolism
  • Drosophila Proteins / antagonists & inhibitors
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Energy Metabolism
  • Forkhead Transcription Factors / metabolism*
  • Glycine N-Methyltransferase / metabolism*
  • Immune System / metabolism*
  • Metabolome
  • Necrosis*
  • Phenotype
  • S-Adenosylmethionine / metabolism*
  • Sarcosine / metabolism
  • Up-Regulation


  • Drosophila Proteins
  • FOXO protein, Drosophila
  • Forkhead Transcription Factors
  • dark protein, Drosophila
  • S-Adenosylmethionine
  • Glycine N-Methyltransferase
  • Sarcosine