The EMAPII Cytokine Is Released from the Mammalian Multisynthetase Complex after Cleavage of Its p43/proEMAPII Component

Shalak, V. F.; Kamińska, M.; Mitnacht-Kraus, Rita; Vandenabeele, Peter; Clauss, Matthias; Mirande, Marc

doi:10.1074/jbc.m100489200

Cited by 122 publications

(132 citation statements)

References 37 publications

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“…This serves as a nonspecific RNA binding domain (29,32), which may function in trans to recruit tRNAs for specific enzyme(s) within the multisynthetase complex. This would result in enhancement of catalytic efficiencies (7,33). Such an effect on aminoacylation has been observed in yeast with the p43 homolog Arc1p, which forms a ternary complex with MetRS and GluRS (34,35).…”

Section: Discussionmentioning

confidence: 95%

A Three-dimensional Working Model of the Multienzyme Complex of Aminoacyl-tRNA Synthetases Based on Electron Microscopic Placements of tRNA and Proteins

Wolfe

Warrington

Treadwell

et al. 2005

Journal of Biological Chemistry

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It has become evident that the process of protein synthesis is performed by many cellular polypeptides acting in concert within the structural confines of protein complexes. In multicellular eukaryotes, one of these assemblies is a multienzyme complex composed of eight proteins that have aminoacyl-tRNA synthetase activities as well as three non-synthetase proteins (p43, p38, and p18) with diverse functions. This study uses electron microscopy and three-dimensional reconstruction to explore the arrangement of proteins and tRNA substrates within this "core" multisynthetase complex. Binding of unfractionated tRNA establishes that these molecules are widely distributed on the exterior of the structure. Binding of gold-labeled tRNALeu places leucyl-tRNA synthetase and the bifunctional glutamyl-/prolyl-tRNA synthetase at the base of this asymmetric "V"-shaped particle. A stable cell line has been produced that incorporates hexahistidine-labeled p43 into the multisynthetase complex. Using a gold-labeled nickel-nitrilotriacetic acid probe, the polypeptides of the p43 dimer have been located along one face of the particle. The results of this and previous studies are combined into an initial three-dimensional working model of the multisynthetase complex. This is the first conceptualization of how the protein constituents and tRNA substrates are arrayed within the structural confines of this multiprotein assembly.It has been known for many years that a "core" complex of aminoacyltRNA synthetases can be isolated from all multicellular eukaryotes (1). Its characteristic composition is three non-synthetase proteins and eight polypeptides having nine aminoacyl-tRNA synthetase activities. With the enzymes abbreviated as the three-letter amino acid name plus RS for the enzyme, the components are ArgRS, AspRS, GluProRS, GlnRS, IleRS, LeuRS, LysRS, MetRS, p43, p38, and p18. Several of these are known dimers, so the total polypeptide count in the multisynthetase complex is at least fifteen. This is a particularly intriguing protein assembly as all of the enzymes catalyze the same reaction, albeit with individual and highly specific substrates. The reaction catalyzed is the covalent attachment of an amino acid to either the 2Ј-or 3Ј-hydroxyl of the 3Ј-terminal adenosine of tRNA. Recent increased interest in these enzymes has been generated by studies indicating that they have roles in a variety of other cellular processes (2-4). Such activities range from cytokine-mediated chemoattraction to priming of reverse transcription of the human immunodeficiency virus, type 1 genome. These enzymes are also viewed as targets in the development of new antimicrobial agents (5). The multisynthetase complex also contains three non-synthetase proteins. The first of these, p18, has been shown to interact with EF-1␥, which may facilitate transfer of aminoacyl-tRNAs to the ribosome (6). Data from yeast two-hybrid screens (7), in vitro binding assays (8), and deletion analysis (9) indicate that p38 functions as a scaffolding protein and appears to be...

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Section: Discussionmentioning

confidence: 95%

A Three-dimensional Working Model of the Multienzyme Complex of Aminoacyl-tRNA Synthetases Based on Electron Microscopic Placements of tRNA and Proteins

Wolfe

Warrington

Treadwell

et al. 2005

Journal of Biological Chemistry

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“…45 In addition to these membrane-mediated mechanisms, several cellular proteins released from apoptotic cells, including p43 aminoacyl tRNA synthases 57 and a ribosomal protein dimer, mediate monocyte attraction. 50 The exposure of calreticulin on the surface of apoptotic cells, its ability to stimulate phagocytes, 13 and its possible release 58 indicate that its potential chemoattractant activity should be examined.…”

Section: Factors Released By Dying Cellsmentioning

confidence: 99%

From regulation of dying cell engulfment to development of anti-cancer therapy

Krysko

Vandenabeele

2007

Cell Death Differ

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Cell death and efficient engulfment of dying cells ensure tissue homeostasis and is involved in pathogenesis. Clearance of dying cells is a complex and dynamic process coordinated by interplay between ligands on dying cell, bridging molecules, and receptors on engulfing cells. In this review, we will discuss recent advances and significance of molecular changes on the surface of dying cells implicated in their recognition and clearance as well as factors released by dying cells that attract macrophages to the site of cell death. It is now becoming apparent that phagocytes use a specific set of mechanisms to discriminate between live and dead cells, and this phenomenon will be illustrated here. Next, we will discuss potential mechanisms by which removal of dying cells could modulate immune responses of phagocytes, in particular of macrophages. Finally, we will address possible strategies for manipulating the immunogenicity of dying cells in experimental cancer therapies.

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“…It was proposed to be located in the center of the complex (11) and binds arginyl-tRNA synthetase (12) as well as tRNA (13) to facilitate the catalysis of the enzyme. Surprisingly, p43 itself is also secreted to work on immune cells and triggers pro-inflammatory response (14,15).…”

mentioning

confidence: 99%

Dose-dependent Biphasic Activity of tRNA Synthetase-associating Factor, p43, in Angiogenesis

Park¹,

Kang²,

Ahn³

et al. 2002

Journal of Biological Chemistry

103

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Mammalian aminoacyl tRNA synthetases form a macromolecular protein complex with three non-enzymatic cofactors. Among these factors, p43 is also secreted to work as a cytokine on endothelial as well as immune cells. Here we investigated the activity of p43 in angiogenesis and determined the related mediators. It promoted the migration of endothelial cells at low dose but induced their apoptosis at high dose. p43 at low concentration activated extracellular signal-regulating kinase, which resulted in the induction and activation of matrix metalloproteinase 9. In contrast, p43 at high concentration activated Jun N-terminal kinase, which mediated apoptosis of endothelial cells. These results suggest that p43 is a novel cytokine playing a dose-dependent biphasic role in angiogenesis.

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The EMAPII Cytokine Is Released from the Mammalian Multisynthetase Complex after Cleavage of Its p43/proEMAPII Component

Cited by 122 publications

References 37 publications

A Three-dimensional Working Model of the Multienzyme Complex of Aminoacyl-tRNA Synthetases Based on Electron Microscopic Placements of tRNA and Proteins

A Three-dimensional Working Model of the Multienzyme Complex of Aminoacyl-tRNA Synthetases Based on Electron Microscopic Placements of tRNA and Proteins

From regulation of dying cell engulfment to development of anti-cancer therapy

Dose-dependent Biphasic Activity of tRNA Synthetase-associating Factor, p43, in Angiogenesis

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