염증성 암세포에서의 caspase-8에 의존적인 lysyl-tRNA synthetase의 exosome을 통한 분비 기전 연구

Abstract

Although lysyl-tRNA synthetase (KRS), an enzyme for protein synthesis, is secreted from cancer cells to trigger inflammatory responses, its secretion mechanism is not understood. Here we show that KRS is secreted via exosomes from cancer cells. KRS is located within the lumen of exosomes and released from the exosomes that are ruptured near the target cells. The N-terminal 12 amino acid of KRS was cleaved by caspase-8 upon starvation. The N-terminal cleavage exposed the PDZ-binding motif located in its C-terminal end. Syntenin bound to the exposed PDZ-binding motif of KRS and facilitated the dissociation of KRS from multi-tRNA synthetase complex for exosomic secretion. The isolated KRS-containing exosomes induced migration and TNF-α secretion of macrophages and KRS showed significant contribution to these activities. These results suggest exosomes as a secretion vehicle for KRS and its functional connection with caspase-8-mediated inflammation provoked by cancer cells.