KRS – A cut away from release in exosomes

Aminoacyl-tRNA synthetases (ARSs), enzymes that normally control protein synthesis, can be secreted and have different activities in the extracellular space, but the mechanism of their secretion is not understood. This study describes the secretion route of the ARS lysyl-tRNA synthetase (KRS) and how this process is regulated by caspase activity, which has been implicated in the unconventional secretion of other proteins. Researchers from Seoul National University show that KRS is secreted from colorectal carcinoma cells within the lumen of exosomes that can trigger an inflammatory response. Caspase-8 cleaved the N-terminal of KRS, thus exposing a PDZ-binding motif located in the C terminus of KRS. Syntenin bound to the exposed PDZ-binding motif of KRS and facilitated the exosomic secretion of KRS dissociated from the multi-tRNA synthetase complex. KRS-containing exosomes released by cancer cells induced macrophage migration, and their secretion of TNF-α and cleaved KRS made a significant contribution to these activities, which suggests a novel mechanism by which caspase-8 may promote inflammation.

Model of KRS exosome release to the extracellular medium

exosomes

KRS (dark blue circle) is normally found in an intracellular multimeric tRNA synthetase complex, where it performs its housekeeping function of binding lysine to tRNA. The C terminus PDZ (violet box) is probably buried and does not bind syntenin (green bar). (1) Upon activation (caused by inflammation or/and starvation), caspase-8 cleaves the first 12 amino acids at the N terminus (orange box) of KRS. The PDZ domain of cleaved KRS (light blue octagon) can bind to syntenin that is localized to the endosomal membrane. (2) Syntenin mediates the incorporation of cleaved KRS in internal vesicles. (3) Multivesicular bodies (MVBs) fuse to the plasma membrane (PM). (4) KRS-positive inflammatory exosomes are released to the extracellular medium. ABD, anticodon binding; CD, catalytic domain.

Kim SB, Kim HR, Park MC, Cho S, Goughnour PC, Han D, Yoon I, Kim Y, Kang T, Song E, Kim P, Choi H, Mun JY, Song C, Lee S, Jung HS, Kim S. (2017) Caspase-8 controls the secretion of inflammatory lysyl-tRNA synthetase in exosomes from cancer cells. J Cell Biol 216(7):2201-2216. [abstract]

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