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- Title
Glutamyl-prolyl-tRNA synthetase 1 coordinates early endosomal anti-inflammatory AKT signaling.
- Authors
Lee, Eun-Young; Kim, Su-Man; Hwang, Jung Hwan; Jang, Song Yee; Park, Shinhye; Choi, Sanghyeon; Lee, Ga Seul; Hwang, Jungwon; Moon, Jeong Hee; Fox, Paul L.; Kim, Sunghoon; Lee, Chul-Ho; Kim, Myung Hee
- 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. 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.
- Subjects
PI3K/AKT pathway; SEPTIC shock; ULCERATIVE colitis; TRANSFER RNA; INFLAMMATORY mediators
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-34226-4