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LysRS Serves as a Key Signaling Molecule in the Immune Response by Regulating Gene Expression
Yannay-Cohen, Nurit,Carmi-Levy, Irit,Kay, Gillian,Yang, Christopher Maolin,Han, Jung Min,Kemeny, D. Michael,Kim, Sunghoon,Nechushtan, Hovav,Razin, Ehud Elsevier 2009 Molecular cell Vol.34 No.5
<P><B>Summary</B></P><P>Lysyl-tRNA synthetase (LysRS) was found to produce diadenosine tetraphosphate (Ap<SUB>4</SUB>A) in vitro more than two decades ago. Here, we used LysRS silencing in mast cells in combination with transfected normal and mutated LysRS to demonstrate in vivo the critical role played by LysRS in the production of Ap<SUB>4</SUB>A in response to immunological challenge. Upon such challenge, LysRS was phosphorylated on serine 207 in a MAPK-dependent manner, released from the multisynthetase complex, and translocated into the nucleus. We previously demonstrated that LysRS forms a complex with MITF and its repressor Hint-1, which is released from the complex by its binding to Ap<SUB>4</SUB>A, enabling MITF to transcribe its target genes. Here, silencing LysRS led to reduced Ap<SUB>4</SUB>A production in immunologically activated cells, which resulted in a lower level of MITF inducible genes. Our data demonstrate that specific LysRS serine 207 phosphorylation regulates Ap<SUB>4</SUB>A production in immunologically stimulated mast cells, thus implying that LysRS is a key mediator in gene regulation.</P>
Structural Switch of Lysyl-tRNA Synthetase between Translation and Transcription
Ofir-Birin, Y.,Fang, P.,Bennett, Steven P.,Zhang, H.M.,Wang, J.,Rachmin, I.,Shapiro, R.,Song, J.,Dagan, A.,Pozo, J.,Kim, S.,Marshall, Alan G.,Schimmel, P.,Yang, X.L.,Nechushtan, H.,Razin, E.,Guo, M. Cell Press 2013 Molecular Cell Vol.49 No.1
Lysyl-tRNA synthetase (LysRS), a component of the translation apparatus, is released from the cytoplasmic multi-tRNA synthetase complex (MSC) to activate the transcription factor MITF in stimulated mast cells through undefined mechanisms. Here we show that Ser207 phosphorylation provokes a new conformer of LysRS that inactivates its translational function but activates its transcriptional function. The crystal structure of an MSC subcomplex established that LysRS is held in the MSC by binding to the N terminus of the scaffold protein p38/AIMP2. Phosphorylation-created steric clashes at the LysRS domain interface disrupt its binding grooves for p38/AIMP2, releasing LysRS and provoking its nuclear translocation. This alteration also exposes the C-terminal domain of LysRS to bind to MITF and triggers LysRS-directed production of the second messenger Ap<SUB>4</SUB>A that activates MITF. Thus our results establish that a single conformational change triggered by phosphorylation leads to multiple effects driving an exclusive switch of LysRS function from translation to transcription.