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 (Ap(4)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(4)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(4)A, enabling MITF to transcribe its target genes. Here, silencing LysRS led to reduced Ap(4)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(4)A production in immunologically stimulated mast cells, thus implying that LysRS is a key mediator in gene regulation.
authors.affiliation: Department of Biochemistry, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Nurit
authors.initials: N
authors.lastname: Yannay-Cohen
authors.forename: Irit
authors.initials: I
authors.lastname: Carmi-Levy
authors.forename: Gillian
authors.initials: G
authors.lastname: Kay
authors.forename: Christopher Maolin
authors.initials: CM
authors.lastname: Yang
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Han
authors.forename: D Michael
authors.initials: DM
authors.lastname: Kemeny
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.forename: Hovav
authors.initials: H
authors.lastname: Nechushtan
authors.forename: Ehud
authors.initials: E
authors.lastname: Razin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D015226:Dinucleoside Phosphates / Q000096:biosynthesis; D005786:Gene Expression Regulation; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D008250:Lysine-tRNA Ligase / Q000378:metabolism / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D015226:Dinucleoside Phosphates; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D012694:Serine; C020733:diadenosine tetraphosphate; D008250:Lysine-tRNA Ligase