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 and Myung Hee Kim ()
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Eun-Young Lee: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Su-Man Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Jung Hwan Hwang: KRIBB
Song Yee Jang: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Shinhye Park: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Sanghyeon Choi: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Ga Seul Lee: KRIBB
Jungwon Hwang: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Jeong Hee Moon: KRIBB
Paul L. Fox: Cleveland Clinic Foundation
Sunghoon Kim: Yonsei University
Chul-Ho Lee: KRIBB
Myung Hee Kim: Korea Research Institute of Bioscience and Biotechnology (KRIBB)

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-34226-4

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