Tryptophan-dependent and -independent secretions of tryptophanyl- tRNA synthetase mediate innate inflammatory responses
Tram Thuy Thuy Nguyen,
Yun Hui Choi,
Won-Kyu Lee,
Yeounjung Ji,
Eunho Chun,
Yi Hyo Kim,
Joo-Eun Lee,
Hyun Suk Jung,
Ji Hun Suh,
Sunghoon Kim,
Mirim Jin
Affiliations
Tram Thuy Thuy Nguyen
Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea
Yun Hui Choi
Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Korea; Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
Won-Kyu Lee
New Drug Development Center, Osong Medical Innovation Foundation, Cheongju 28160, Korea
Yeounjung Ji
Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Korea; Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea
Eunho Chun
Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea
Yi Hyo Kim
Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea
Joo-Eun Lee
Department of Biochemistry, Kangwon National University, Chuncheon 24341, Korea
Hyun Suk Jung
Department of Biochemistry, Kangwon National University, Chuncheon 24341, Korea
Ji Hun Suh
Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy & College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon 21983, Korea
Sunghoon Kim
Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy & College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon 21983, Korea
Mirim Jin
Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea; Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Korea; Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Korea; Corresponding author
Summary: 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.
