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

Author

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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)
    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))

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.

Suggested Citation

  • 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, 2022. "Glutamyl-prolyl-tRNA synthetase 1 coordinates early endosomal anti-inflammatory AKT signaling," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34226-4
    DOI: 10.1038/s41467-022-34226-4
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    References listed on IDEAS

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    1. Laura Braccini & Elisa Ciraolo & Carlo C. Campa & Alessia Perino & Dario L. Longo & Gianpaolo Tibolla & Marco Pregnolato & Yanyan Cao & Beatrice Tassone & Federico Damilano & Muriel Laffargue & Enzo C, 2015. "PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    2. Abul Arif & Fulvia Terenzi & Alka A. Potdar & Jie Jia & Jessica Sacks & Arnab China & Dalia Halawani & Kommireddy Vasu & Xiaoxia Li & J. Mark Brown & Jie Chen & Sara C. Kozma & George Thomas & Paul L., 2017. "EPRS is a critical mTORC1–S6K1 effector that influences adiposity in mice," Nature, Nature, vol. 542(7641), pages 357-361, February.
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