MsrB1-regulated GAPDH oxidation plays programmatic roles in shaping metabolic and inflammatory signatures during macrophage activation

Hyun Jung Yoo, Dong Wook Choi, Yeon Jin Roh, Yoon Mi Lee, Ji Hong Lim, Soohak Eo, Ho Jae Lee, Na Young Kim, Seohyun Kim, Sumin Cho, Gyumin Im, Byung Cheon Lee, Ji Hyung Kim

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Classically activated pro-inflammatory macrophages are generated from naive macrophages by pro-inflammatory cues that dynamically reprogram their fuel metabolism toward glycolysis. This increases their intracellular reactive oxygen species (ROS) levels, which then activate the transcription and release of pro-inflammatory mediators. Our study on mice that lack methionine sulfoxide reductase (Msr)-B1 shows that the resulting partial loss of protein methionine reduction in pro-inflammatory macrophages creates a unique metabolic signature characterized by altered fuel utilization, including glucose and pyruvate. This change also associates with hyper-inflammation that is at least partly due to sustained oxidation of an exposed methionine residue (M44) on glyceraldehyde 3-phosphate dehydrogenase (GAPDH), thereby inducing GAPDH aggregation, inflammasome activation, and subsequent increased interleukin (IL)-1β secretion. Since MsrB1-knockout mice exhibit increased susceptibility to lipopolysaccharide (LPS)-induced sepsis, the MsrB1-GAPDH axis may be a key molecular mechanism by which protein redox homeostasis controls the metabolic profile of macrophages and thereby regulates their functions.

Original languageEnglish
Article number111598
JournalCell Reports
Volume41
Issue number6
DOIs
Publication statusPublished - 2022 Nov 8

Keywords

  • CP: Metabolism
  • GAPDH
  • inflammasome
  • macrophage
  • metabolic reprogramming
  • MsrB1
  • ROS
  • sepsis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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