Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response

Park, Sang Gyu; Kim, Hye Jin; Min, You; Choi, Eung‐Chil; Shin, Young Kee; Park, Bum-Joon; Lee, Sang Won; Kim, Sung Hoon

doi:10.1073/pnas.0500226102

Cited by 158 publications

(146 citation statements)

References 53 publications

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“…Aminoacyl-tRNA synthetases have been shown to function in a wide array of cellular processes that are distinct from aminoacylation and changes in oligomeric state, as well as posttranslational modifications have been shown to regulate these alternate functions (37)(38)(39)). An intriguing observation that highlights the dynamic nature of LysRS within the cell, is illustrated by its mobilization to the nucleus (37).…”

Section: Discussionmentioning

confidence: 99%

Dual Role for Motif 1 Residues of Human Lysyl-tRNA Synthetase in Dimerization and Packaging into HIV-1

Dewan

Wei

Kleiman

et al. 2012

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Dual Role for Motif 1 Residues of Human Lysyl-tRNA Synthetase in Dimerization and Packaging into HIV-1

Dewan

Wei

Kleiman

et al. 2012

Journal of Biological Chemistry

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“…The interaction of p53 with AIMP2 was also tested by using a yeast two-hybrid assay. LexA-p53 with B42-AIMP2, but not with B42-AIMP1 (2, 4) and -lysyl-tRNA synthetase (KRS) (14,21), permitted yeast cell growth on leucine-depleted medium (Fig. 4C), suggesting a specific interaction between p53 and AIMP2.…”

Section: Aimp2 Controls the P53mentioning

confidence: 99%

AIMP2/p38, the scaffold for the multi-tRNA synthetase complex, responds to genotoxic stresses via p53

Han¹,

Park²,

Park³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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105

108

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AIMP2/p38 is a scaffolding protein required for the assembly of the macromolecular tRNA synthetase complex. Here, we describe a previously unknown function for AIMP2 as a positive regulator of p53 in response to genotoxic stresses. Depletion of AIMP2 increased resistance to DNA damage-induced apoptosis, and introduction of AIMP2 into AIMP2-deficient cells restored the susceptibility to apoptosis. Upon DNA damage, AIMP2 was phosphorylated, dissociated from the multi-tRNA synthetase complex, and translocated into the nuclei of cells. AIMP2 directly interacts with p53, thereby preventing MDM2-mediated ubiquitination and degradation of p53. Mutations in AIMP2, affecting its interaction with p53, hampered its ability to activate p53. Nutlin-3 recovered the level of p53 and the susceptibility to UV-induced cell death in AIMP2-deficient cells. This work demonstrates that AIMP2, a component of the translational machinery, functions as proapoptotic factor via p53 in response to DNA damage.A minoacyl-tRNA synthetases (ARSs) are the enzymes that ligate specific amino acids to tRNAs before protein synthesis. In higher eukaryotic systems, nine different ARSs form an intriguing macromolecular complex with three nonenzymatic factors called ARS-interacting, multifunctional proteins (AIMPs) (1, 2). Many of these complex-forming ARSs, as well as AIMPs, play diverse regulatory roles that are not directly related to protein synthesis (2). Among the three AIMPs, AIMP1 is secreted as a cytokine working in immune, angiogenesis, and wound-healing processes (3-7) and also functions as a hormone controlling glucose homeostasis (8). AIMP3 is a tumor suppressor required for chromosome integrity (9, 10). Although AIMP2 is critical for the assembly of the multi-ARS complex (11), it also suppresses cell proliferation via down-regulation of c-Myc (12). In addition, AIMP2 was shown to be involved in Parkinson's disease, inducing neural cell death (13). However, it is yet to be determined how AIMP2 is involved in the control of cell death. In this work, we investigated the functional significance and molecular behavior of AIMP2 during the control of cell death and the relationship of AIMP2 associated with the multi-ARS complex and its proapoptotic activity. Results AIMP2-Deficient Cells AreResistant to Cell Death. To see the importance of AIMP2 during the control of cell death, we subjected 12.5-d AIMP2 ϩ/ϩ and AIMP2 Ϫ/Ϫ mouse embryonic fibroblasts (MEFs) to UV irradiation and compared their apoptotic sensitivity. The apoptotic cells, indicated by the subG1 portion, were increased Ϸ3-fold by UV irradiation in AIMP2 ϩ/ϩ but not in AIMP2 Ϫ/Ϫ cells (Fig. 1A). Transfection of AIMP2 into AIMP2 Ϫ/Ϫ MEFs restored the apoptotic sensitivity to UV irradiation (Fig. 1B). We also compared the apoptotic response of AIMP2 ϩ/ϩ and AIMP2 Ϫ/Ϫ MEFs to UV irradiation by monitoring caspase-3 activation. Procaspase-3 cleavage resulting in caspase-3 generation was observed in AIMP2 ϩ/ϩ but not in AIMP2 Ϫ/Ϫ cells (Fig. 1C). Suppression of AIMP2 via gene-specific siRNA...

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“…As another example, when released from the MSC, human glutaminyltRNA synthetase specifically interacts with the apoptosis signalregulating kinase 1 (ASK1) and inhibits ASK1-mediated apoptosis by inhibiting its kinase activity (5). Another component of the complex, lysyl-tRNA synthetase (LysRS), was recently shown to be secreted and to trigger a proinflammatory response (6). In addition, all three accessory proteins in the MSC, p43, p38, and p18 (also known as AIMP1, AIMP2, and AIMP3), have also been shown to have cytokine activities or to participate in different cell regulatory events (7,8).…”

mentioning

confidence: 99%

Crystal structure of tetrameric form of human lysyl-tRNA synthetase: Implications for multisynthetase complex formation

Guo

Ignatov

Musier‐Forsyth

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

114

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In mammals, many aminoacyl-tRNA synthetases are bound together in a multisynthetase complex (MSC) as a reservoir of procytokines and regulation molecules for functions beyond aminoacylation. The ␣2 homodimeric lysyl-tRNA synthetase (LysRS) is tightly bound in the MSC and, under specific conditions, is secreted to trigger a proinflammatory response. Results by others suggest that ␣2 LysRS is tightly bound into the core of the MSC with homodimeric ␤2 p38, a scaffolding protein that itself is multifunctional. Not understood is how the two dimeric proteins combine to make a presumptive ␣2␤2 heterotetramer and, in particular, the location of the surfaces on LysRS that would accommodate the p38 interactions. Here we present a 2.3-Å crystal structure of a tetrameric form of human LysRS. The relatively loose (as seen in solution) tetramer interface is assembled from two eukaryotespecific sequences, one in the catalytic-and another in the anticodon-binding domain. This same interface is predicted to provide unique determinants for interaction with p38. The analyses suggest how the core of the MSC is assembled and, more generally, that interactions and functions of synthetases can be built and regulated through dynamic protein-protein interfaces. These interfaces are created from small adaptations to what is otherwise a highly conserved (through evolution) polypeptide sequence.AIMP2 ͉ aminoacyl-tRNA synthetase ͉ p38

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Human lysyl-tRNA synthetase is secreted to trigger proinflammatory response

Cited by 158 publications

References 53 publications

Dual Role for Motif 1 Residues of Human Lysyl-tRNA Synthetase in Dimerization and Packaging into HIV-1

Dual Role for Motif 1 Residues of Human Lysyl-tRNA Synthetase in Dimerization and Packaging into HIV-1

AIMP2/p38, the scaffold for the multi-tRNA synthetase complex, responds to genotoxic stresses via p53

Crystal structure of tetrameric form of human lysyl-tRNA synthetase: Implications for multisynthetase complex formation

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