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

doi:10.1038/s41467-022-34226-4

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

Department of Pharmacy

Research output: Contribution to journal › Article › peer-review

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 language	English
Article number	6455
Journal	Nature communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-34226-4
Publication status	Published - 2022 Dec

Bibliographical note

Funding Information:
We thank all members of the Infection and Immunity Research Laboratory at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) for technical assistance and helpful discussions. We would like to thank Dr. Won Do Heo at KAIST for his helpful advice on confocal microscopy experiments. This work was supported by a Samsung Science and Technology Foundation grant (SSTF-BA1902-04), the National Research Council of Science & Technology (No. CAP20013-000), and the National Research Foundation of Korea (NRF-2021M3A9I4022934) grants funded by MSIT, and the KRIBB Initiative Program to M.H.K.

Funding Information:
We thank all members of the Infection and Immunity Research Laboratory at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) for technical assistance and helpful discussions. We would like to thank Dr. Won Do Heo at KAIST for his helpful advice on confocal microscopy experiments. This work was supported by a Samsung Science and Technology Foundation grant (SSTF-BA1902-04), the National Research Council of Science & Technology (No. CAP20013-000), and the National Research Foundation of Korea (NRF-2021M3A9I4022934) grants funded by MSIT, and the KRIBB Initiative Program to M.H.K.

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

All Science Journal Classification (ASJC) codes

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
General
Physics and Astronomy(all)

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10.1038/s41467-022-34226-4

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@article{9a746c040ab543e6acbb4a1477921e42,

title = "Glutamyl-prolyl-tRNA synthetase 1 coordinates early endosomal anti-inflammatory AKT signaling",

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.",

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

note = "Funding Information: We thank all members of the Infection and Immunity Research Laboratory at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) for technical assistance and helpful discussions. We would like to thank Dr. Won Do Heo at KAIST for his helpful advice on confocal microscopy experiments. This work was supported by a Samsung Science and Technology Foundation grant (SSTF-BA1902-04), the National Research Council of Science & Technology (No. CAP20013-000), and the National Research Foundation of Korea (NRF-2021M3A9I4022934) grants funded by MSIT, and the KRIBB Initiative Program to M.H.K. Funding Information: We thank all members of the Infection and Immunity Research Laboratory at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) for technical assistance and helpful discussions. We would like to thank Dr. Won Do Heo at KAIST for his helpful advice on confocal microscopy experiments. This work was supported by a Samsung Science and Technology Foundation grant (SSTF-BA1902-04), the National Research Council of Science & Technology (No. CAP20013-000), and the National Research Foundation of Korea (NRF-2021M3A9I4022934) grants funded by MSIT, and the KRIBB Initiative Program to M.H.K. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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doi = "10.1038/s41467-022-34226-4",

language = "English",

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AU - Lee, Eun Young

AU - Kim, Su Man

AU - Hwang, Jung Hwan

AU - Jang, Song Yee

AU - Park, Shinhye

AU - Choi, Sanghyeon

AU - Lee, Ga Seul

AU - Hwang, Jungwon

AU - Moon, Jeong Hee

AU - Fox, Paul L.

AU - Kim, Sunghoon

AU - Lee, Chul Ho

AU - Kim, Myung Hee

N1 - Funding Information: We thank all members of the Infection and Immunity Research Laboratory at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) for technical assistance and helpful discussions. We would like to thank Dr. Won Do Heo at KAIST for his helpful advice on confocal microscopy experiments. This work was supported by a Samsung Science and Technology Foundation grant (SSTF-BA1902-04), the National Research Council of Science & Technology (No. CAP20013-000), and the National Research Foundation of Korea (NRF-2021M3A9I4022934) grants funded by MSIT, and the KRIBB Initiative Program to M.H.K. Funding Information: We thank all members of the Infection and Immunity Research Laboratory at the Korea Research Institute of Bioscience and Biotechnology (KRIBB) for technical assistance and helpful discussions. We would like to thank Dr. Won Do Heo at KAIST for his helpful advice on confocal microscopy experiments. This work was supported by a Samsung Science and Technology Foundation grant (SSTF-BA1902-04), the National Research Council of Science & Technology (No. CAP20013-000), and the National Research Foundation of Korea (NRF-2021M3A9I4022934) grants funded by MSIT, and the KRIBB Initiative Program to M.H.K. Publisher Copyright: © 2022, The Author(s).

PY - 2022/12

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N2 - 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.

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

Abstract

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