While cytoplasmic tryptophanyl-tRNA synthetase (WARS1) ligates tryptophan (Trp) to its cognate tRNAs for protein synthesis, it also plays a role as an innate immune activator in extracellular space. However, its secretion mechanism remains elusive. Here, we report that in response to stimuli, WARS1 can be secreted via two distinct pathways: via Trp-dependent secretion of naked protein and via Trp-independent plasma-membrane-derived vesicles (PMVs). In the direct pathway, Trp binding to WARS1 induces a “closed” conformation, generating a hydrophobic surface and basic pocket. The Trp-bound WARS1 then binds stable phosphatidylinositol (4,5)-biphosphate and inner plasma membrane leaflet, passing across the membrane. In the PMV-mediated secretion, WARS1 recruits calpain 2, which is activated by calcium. WARS1 released from PMVs induces inflammatory responses in vivo. These results provide insights into the secretion mechanisms of WARS1 and improve our understanding of how WARS1 is involved in the control of local and systemic inflammation upon infection.
|Publication status||Published - 2023 Jan 31|
Bibliographical noteFunding Information:
This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation ( NRF ) of the Korean government ( MSIT ) (grant numbers NRF-2019M3E5D5064771 and NRF-2021R1A3B1076605 ); the Korea Health Technology R&D project through the Korea Health Industry Development Institute ( KHIDI ), funded by the Ministry of Health and Welfare ; the Republic of Korea (grant number: HI20C0015 ); the Daegu-Gyongbuk/Osong Medical Cluster R&D project funded by the Ministry of Science and ICT ; the Ministry of Trade, Industry and Energy ; the Ministry of Health and Welfare , Republic of Korea (grant number: HI19C0763 ); and the Yonsei University Research Fund (grant number 2020-22-0356 ).
© 2022 The Author(s)
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)