Journal
NATURE COMMUNICATIONS
Volume 13, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34226-4
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Funding
- Samsung Science and Technology Foundation [SSTF-BA1902-04]
- National Research Council of Science Technology [CAP20013-000]
- National Research Foundation of Korea - MSIT [NRF-2021M3A9I4022934]
- KRIBB Initiative Program
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This study reveals the critical role of EPRS1 in coordinating AKT signaling for anti-inflammatory responses, shedding light on potential therapeutic targets for inflammatory diseases.
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 GSK3 beta 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. The PI3K/AKT signaling pathway is carefully regulated in specific cellular compartments. Lee and colleagues show that the housekeeping gene glutamyl-prolyl-tRNA synthetase 1 coordinates early endosome-specific AKT signaling necessary for inflammation resolution.
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