Editors' ChoiceTranscriptional Regulation

Not Just a Translator

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Science Signaling  23 Jun 2009:
Vol. 2, Issue 76, pp. ec205
DOI: 10.1126/scisignal.276ec205

Aminoacyl-tRNA synthetases (aaRSs) covalently attach amino acids to tRNAs to form aminoacyl-tRNAs for mRNA translation. Some aaRSs, including lysyl-tRNA synthetase (LysRS), are part of the multisynthetase complex (MSC), which is located in the cytosol. aaRSs also produce the nucleotide diadenosine tetraphosphate (Ap4A), which appears to be produced during cellular stresses. LysRS is a major producer of this nucleotide, particularly when it is not associated with the MSC. In addition, LysRS associates with the microphthalmia-associated transcription factor in the nucleus, and higher Ap4A concentrations are associated with increased MITF transcriptional activity. Previous work indicated that phosphorylation of aaRSs increases Ap4A production without affecting the rate of aminoacylation, although the underlying mechanism was not known. Yannay-Cohen et al. found that in rat basophilic leukemia (RBL) mast cells transfected with short interfering RNA (siRNA) directed against LysRS, Ap4A accumulation in response to activation [aggregation of the IgE receptor (FcεRI) by antigen bound to IgE] was blocked. In nonactivated RBL cells, LysRS was mostly associated with the MSC in the cytosol; however, upon activation of RBL cells by FcεRI aggregation, LysRS dissociated from the MSC and translocated to the nucleus. Treatment of RBL cells before FcεRI aggregation with the MEK inhibitor U0126, but not with the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, blocked phosphorylation of Ser207 of LysRS. This phosphorylation was required for dissociation of LysRS from the MSC and translocation of LysRS from the cytosol to the nucleus. siRNA knockdown of LysRS reduced the transcript abundance for two MITF target genes, tryptophan hydroxylase (TPH) and mast cell protease 5 (MCP5), and this effect was also seen with pretreatment of RBL cells before FcεRI aggregation with U0126. Thus, the ERK pathway promotes phosphorylation of LysRS during mast cell activation, which switches its function from a component of the translational machinery to a transcriptional regulator.

N. Yannay-Cohen, I. Carmi-Levy, G. Kay, C. Maolin Yang, J. M. Han, D. M. Kemeny, S. Kim, H. Nechushtan, E. Razin, LysRS serves as a key signaling molecule in the immune response by regulating gene expression. Mol. Cell 34, 603–611 (2009). [PubMed]

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