한빛사 논문
Eun-Young Lee 1 , Su-Man Kim 1, Jung Hwan Hwang2, Song Yee Jang1,3, Shinhye Park1, Sanghyeon Choi1, Ga Seul Lee3, Jungwon Hwang 1, Jeong Hee Moon3, Paul L. Fox4, Sunghoon Kim 5, Chul-Ho Lee 2 & Myung Hee Kim 1
1Microbiome Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
2Laboratory Animal Resource Center, KRIBB, Daejeon 34141, Korea.
3Core Research Facility & Analysis Center, KRIBB, Daejeon 34141, Korea.
4Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
5Medicinal Bioconvergence Research Center, College of Pharmacy and College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon 21983, Korea.
Corresponding authors: Correspondence to Eun-Young Lee or Myung Hee Kim.
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.
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