p43 is one of the three auxiliary components invariably associated with nine aminoacyl-tRNA synthetases as a multienzyme complex ubiquitous to all eukaryotic cells from flies to humans. The cDNA encoding the hamster protein was isolated by using mixed oligonucleotides deduced from peptide sequences. The 359-amino acid protein is the hamster homologue of the recently reported murine and human EMAP II cytokine implicated in a variety of inflammatory disorders. The sequence of several proEMAP II proteins suggests that the p43 component of the complex is the precursor of the active mature cytokine after cleavage at a conserved Asp residue. The COOH-terminal moiety of p43 is also homologous to polypeptide domains found in bacterial methionyl-or phenylalanyl-tRNA synthetases and in the yeast Arc1p/G4p1 protein that associates with yeast methionyl-tRNA synthetase. Our results implicate the COOH-terminal moiety of p43 as a RNA binding domain. In the native state, as a component of the multisynthetase complex, p43 may be required for tRNA channeling and, after proteolytic processing occurring in tumor cells, would acquire inflammatory properties possibly related to apoptosis. The release of a truncated p43 from the complex could be involved in mediation of the signaling of tumor cells and stimulation of an acute inflammatory response.Aminoacyl-tRNA synthetases catalyze the activation of their cognate amino acid and transfer to the relevant tRNA. In mammals, this family of enzyme contributes two distinct high molecular mass structures: a complex made of nine synthetases and a complex involving valyl-tRNA synthetase and the ␣, , ␥, and ␦ subunits of elongation factor 1. The ten other aminoacyltRNA synthetases are generally described as free enzymes (1-3). The multisynthetase complex contains the nine aminoacyl-tRNA synthetase activities for amino acids Glu, Pro, Ile, Leu, Met, Gln, Lys, Arg, and Asp and the three auxiliary proteins with masses of 18, 38, and 43 kDa. It is ubiquitous to all coelomate metazoan species from arthropods to humans (4). Immunoprecipitation experiments demonstrated the tight association of all of these components (5-7). Electron microscopy studies showed a fairly elongated U-shaped structure (8). Although the three nonsynthetase components were invariably encountered in this complex, their structural or functional role within this multi-subunit structure was not established.We have recently reported the cloning of the cDNA encoding the p18 component of the complex (9). It shares sequence homology with a protein domain recovered in the NH 2 -terminal polypeptide extension of human valyl-tRNA synthetase and in the NH 2 -terminal domains of the  and ␥ subunits of elongation factor 1. In the valyl-tRNA synthetase⅐EF-1H complex, this domain has been involved in protein-protein interaction between the  and ␥ subunits of the eukaryotic elongation factor EF-1H (10) or between valyl-tRNA synthetase and EF-1H (11). This led us to suggest that p18 is involved in anchoring the multisynthetase complex to th...
Parkinson's disease (PD) is a severe neurological disorder, characterized by the progressive degeneration of the dopaminergic nigrostriatal pathway and the presence of Lewy bodies (LBs). The discovery of genes responsible for familial forms of the disease has provided insights into its pathogenesis. Mutations in the parkin gene, which encodes an E3 ubiquitin-protein ligase involved in the ubiquitylation and proteasomal degradation of specific protein substrates, have been found in nearly 50% of patients with autosomal-recessive early-onset parkinsonism. The abnormal accumulation of substrates due to loss of Parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. Here, we demonstrate that Parkin interacts with, ubiquitylates and promotes the degradation of p38, a key structural component of the mammalian aminoacyl-tRNA synthetase complex. We found that the ubiquitylation of p38 is abrogated by truncated variants of Parkin lacking essential functional domains, but not by the pathogenic Lys161Asn point mutant. Expression of p38 in COS7 cells resulted in the formation of aggresome-like inclusions in which Parkin was systematically sequestered. In the human dopaminergic neuroblastoma-derived SH-SY5Y cell line, Parkin promoted the formation of ubiquitylated p38-positive inclusions. Moreover, the overexpression of p38 in SH-SY5Y cells caused significant cell death against which Parkin provided protection. Analysis of p38 expression in the human adult midbrain revealed strong immunoreactivity in normal dopaminergic neurons and the labeling of LBs in idiopathic PD. This suggests that p38 plays a role in the pathogenesis of PD, opening the way for a detailed examination of its potential non-canonical role in neurodegeneration.
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