LysRS Serves as a Key Signaling Molecule in the Immune Response by Regulating Gene Expression

Nurit Yannay-Cohen; Irit Carmi-Levy; Gillian Kay; Christopher Maolin Yang; Jung Min Han; D. Michael Kemeny; Sunghoon Kim; Hovav Nechushtan; Ehud Razin

doi:10.1016/j.molcel.2009.05.019

LysRS Serves as a Key Signaling Molecule in the Immune Response by Regulating Gene Expression

Nurit Yannay-Cohen, Irit Carmi-Levy, Gillian Kay, Christopher Maolin Yang, Jung Min Han, D. Michael Kemeny, Sunghoon Kim, Hovav Nechushtan, Ehud Razin

Research output: Contribution to journal › Article › peer-review

124 Citations (Scopus)

Abstract

Lysyl-tRNA synthetase (LysRS) was found to produce diadenosine tetraphosphate (Ap₄A) 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 Ap₄A 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 Ap₄A, enabling MITF to transcribe its target genes. Here, silencing LysRS led to reduced Ap₄A 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 Ap₄A production in immunologically stimulated mast cells, thus implying that LysRS is a key mediator in gene regulation.

Original language	English
Pages (from-to)	603-611
Number of pages	9
Journal	Molecular Cell
Volume	34
Issue number	5
DOIs	https://doi.org/10.1016/j.molcel.2009.05.019
Publication status	Published - 2009 Jun 12

Bibliographical note

Funding Information:
This work was supported by the United States Binational Science Foundation (E.R., 2003-009); the Israeli Academy of Science (E.R., 144/04); the German-Israel Foundation for Scientific Research and Development (E.R., I-726-10.2); the Morasha Foundation Fund (H.N.); the Acceleration Research of KOSEF (S.K., 2009-0063498); and the 21st Frontier Functional Proteomics Research (S.K., FPR0881-250). I.C.-L. was supported by the Canadian Friends of Hebrew University. We would like to thank Dr. Mario Lebendiker from The Protein Purification Facility, Wolfson Centre for Applied Structural Biology, Hebrew University of Jerusalem, for his help in gel filtration chromatography.

All Science Journal Classification (ASJC) codes

Molecular Biology
Cell Biology

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10.1016/j.molcel.2009.05.019

Cite this

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title = "LysRS Serves as a Key Signaling Molecule in the Immune Response by Regulating Gene Expression",

abstract = "Lysyl-tRNA synthetase (LysRS) was found to produce diadenosine tetraphosphate (Ap4A) 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 Ap4A 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 Ap4A, enabling MITF to transcribe its target genes. Here, silencing LysRS led to reduced Ap4A 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 Ap4A production in immunologically stimulated mast cells, thus implying that LysRS is a key mediator in gene regulation.",

author = "Nurit Yannay-Cohen and Irit Carmi-Levy and Gillian Kay and Yang, {Christopher Maolin} and Han, {Jung Min} and Kemeny, {D. Michael} and Sunghoon Kim and Hovav Nechushtan and Ehud Razin",

note = "Funding Information: This work was supported by the United States Binational Science Foundation (E.R., 2003-009); the Israeli Academy of Science (E.R., 144/04); the German-Israel Foundation for Scientific Research and Development (E.R., I-726-10.2); the Morasha Foundation Fund (H.N.); the Acceleration Research of KOSEF (S.K., 2009-0063498); and the 21st Frontier Functional Proteomics Research (S.K., FPR0881-250). I.C.-L. was supported by the Canadian Friends of Hebrew University. We would like to thank Dr. Mario Lebendiker from The Protein Purification Facility, Wolfson Centre for Applied Structural Biology, Hebrew University of Jerusalem, for his help in gel filtration chromatography. ",

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AU - Yannay-Cohen, Nurit

AU - Carmi-Levy, Irit

AU - Kay, Gillian

AU - Yang, Christopher Maolin

AU - Han, Jung Min

AU - Kemeny, D. Michael

AU - Kim, Sunghoon

AU - Nechushtan, Hovav

AU - Razin, Ehud

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Y1 - 2009/6/12

N2 - Lysyl-tRNA synthetase (LysRS) was found to produce diadenosine tetraphosphate (Ap4A) 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 Ap4A 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 Ap4A, enabling MITF to transcribe its target genes. Here, silencing LysRS led to reduced Ap4A 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 Ap4A production in immunologically stimulated mast cells, thus implying that LysRS is a key mediator in gene regulation.

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LysRS Serves as a Key Signaling Molecule in the Immune Response by Regulating Gene Expression

Abstract

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