Caspase-8 controls the secretion of inflammatory lysyl-tRNA synthetase in exosomes from cancer cells

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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. We 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-alpha and cleaved KRS made a significant contribution to these activities, which suggests a novel mechanism by which caspase-8 may promote inflammation.
Publisher
ROCKEFELLER UNIV PRESS
Issue Date
2017-07
Language
English
Article Type
Article
Keywords

GREEN FLUORESCENT PROTEIN; PDZ-BINDING MOTIF; DEPENDENT MANNER; IDENTIFICATION; DEATH; ALIX; PROLIFERATION; POLARIZATION; TRANSLATION; MACROPHAGES

Citation

JOURNAL OF CELL BIOLOGY, v.216, no.7, pp.2201 - 2216

ISSN
0021-9525
DOI
10.1083/jcb.201605118
URI
http://hdl.handle.net/10203/225091
Appears in Collection
NT-Journal Papers(저널논문)
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