title: Importin beta plays an essential role in the regulation of the LysRS-Ap(4)A pathway in immunologically activated mast cells.
abstract: We recently reported that diadenosine tetraphosphate hydrolase (Ap(4)A hydrolase) plays a critical role in gene expression via regulation of intracellular Ap(4)A levels. This enzyme serves as a component of our newly described lysyl tRNA synthetase (LysRS)-Ap(4)A biochemical pathway that is triggered upon immunological challenge. Here we explored the mechanism of this enzyme's translocation into the nucleus and found its immunologically dependent association with importin beta. Silencing of importin beta prevented Ap(4)A hydrolase nuclear translocation and affected the local concentration of Ap(4)A, which led to an increase in microphthalmia transcription factor (MITF) transcriptional activity. Furthermore, immunological activation of mast cells resulted in dephosphorylation of Ap(4)A hydrolase, which changed the hydrolytic activity of the enzyme.
authors.affiliation: Department of Biochemistry and Molecular Biology, The Institute for Medical Research-Israel-Canada, The Hebrew University-Hadassah Medical School, POB 12272, Jerusalem 91120, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Carmi-Levy
authors.forename: Alex
authors.initials: A
authors.lastname: Motzik
authors.forename: Yifat
authors.initials: Y
authors.lastname: Ofir-Birin
authors.forename: Zohar
authors.initials: Z
authors.lastname: Yagil
authors.forename: Christopher Maolin
authors.initials: CM
authors.lastname: Yang
authors.forename: David Michael
authors.initials: DM
authors.lastname: Kemeny
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Han
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.forename: Gillian
authors.initials: G
authors.lastname: Kay
authors.forename: Hovav
authors.initials: H
authors.lastname: Nechushtan
authors.forename: Ryo
authors.initials: R
authors.lastname: Suzuki
authors.forename: Juan
authors.initials: J
authors.lastname: Rivera
authors.forename: Ehud
authors.initials: E
authors.lastname: Razin
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D015226:Dinucleoside Phosphates / Q000032:analysis; D005434:Flow Cytometry; D015870:Gene Expression; D007073:Immunoglobulin E / Q000276:immunology; D047468:Immunoprecipitation; D008250:Lysine-tRNA Ligase / Q000235:genetics / Q000378:metabolism*; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics; D016133:Polymerase Chain Reaction; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D028961:beta Karyopherins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015226:Dinucleoside Phosphates; D051739:Microphthalmia-Associated Transcription Factor; D034741:RNA, Small Interfering; D028961:beta Karyopherins; D007073:Immunoglobulin E; C020733:diadenosine tetraphosphate; D017766:Acid Anhydride Hydrolases; C020023:bis(5'-nucleosyl)tetraphosphatase (asymmetrical); D008250:Lysine-tRNA Ligase