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Park, Joon Sung,Park, Min Chul,Lee, Ki-Young,Goughnour, Peter C.,Jeong, Seung Jae,Kim, Hyoun Sook,Kim, Hyun-Jung,Lee, Bong-Jin,Kim, Sunghoon,Han, Byung Woo Elsevier 2018 INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES Vol.120 No.1
<P><B>Abstract</B></P> <P>Asparaginyl-tRNA synthetase (NRS) is not only essential in protein translation but also associated with autoimmune diseases. Particularly, patients with antibodies that recognize NRS often develop interstitial lung disease (ILD). However, the underlying mechanism of how NRS is recognized by immune cells and provokes inflammatory responses is not well-understood. Here, we found that the crystal structure of the unique N-terminal extension domain of human NRS (named as UNE-N, where -N denotes NRS) resembles that of the chemotactic N-terminal domain of NRS from a filarial nematode, <I>Brugia malayi</I>, which recruits and activates specific immune cells by interacting with CXC chemokine receptor 1 and 2. UNE-N induced migration of CC chemokine receptor 3 (CCR3)-expressing cells. The chemokine activity of UNE-N was significantly reduced by suppressing CCR3 expression with CCR3-targeting siRNA, and the loop3 region of UNE-N was shown to interact mainly with the extracellular domains of CCR3 in nuclear magnetic resonance perturbation experiments. Based on these results, evolutionarily acquired UNE-N elicits chemokine activities that would promote NRS-CCR3-mediated proinflammatory signaling in ILD.</P>
Caspase-8 controls the secretion of inflammatory lysyl-tRNA synthetase in exosomes from cancer cells
Kim, Sang Bum,Kim, Hye Rim,Park, Min Chul,Cho, Seongmin,Goughnour, Peter C.,Han, Daeyoung,Yoon, Ina,Kim, YounHa,Kang, Taehee,Song, Eunjoo,Kim, Pilhan,Choi, Hyosun,Mun, Ji Young,Song, Chihong,Lee, Sang Rockefeller University Press 2017 The Journal of cell biology Vol.216 No.7
<P>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-α and cleaved KRS made a significant contribution to these activities, which suggests a novel mechanism by which caspase-8 may promote inflammation.</P>