Glutamyl-prolyl-tRNA synthetase 1 coordinates early endosomal anti-inflammatory AKT signaling

Eun Young Lee, Su Man Kim, Jung Hwan Hwang, Song Yee Jang, Shinhye Park, Sanghyeon Choi, Ga Seul Lee, Jungwon Hwang, Jeong Hee Moon, Paul L. Fox, Sunghoon Kim, Chul Ho Lee, Myung Hee Kim

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

The AKT signaling pathway plays critical roles in the resolution of inflammation. However, the underlying mechanisms of anti-inflammatory regulation and signal coordination remain unclear. Here, we report that anti-inflammatory AKT signaling is coordinated by glutamyl-prolyl-tRNA synthetase 1 (EPRS1). Upon inflammatory activation, AKT specifically phosphorylates Ser999 of EPRS1 in the cytoplasmic multi-tRNA synthetase complex, inducing release of EPRS1. EPRS1 compartmentalizes AKT to early endosomes via selective binding to the endosomal membrane lipid phosphatidylinositol 3-phosphate and assembles an AKT signaling complex specific for anti-inflammatory activity. These events promote AKT activation-mediated GSK3β phosphorylation, which increase anti-inflammatory cytokine production. EPRS1-deficient macrophages do not assemble the early endosomal complex and consequently exacerbate inflammation, decreasing the survival of EPRS1-deficient mice undergoing septic shock and ulcerative colitis. Collectively, our findings show that the housekeeping protein EPRS1 acts as a mediator of inflammatory homeostasis by coordinating compartment-specific AKT signaling.

Original languageEnglish
Article number6455
JournalNature communications
Volume13
Issue number1
DOIs
Publication statusPublished - 2022 Dec

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • General Biochemistry,Genetics and Molecular Biology
  • General Physics and Astronomy

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