title: Identification of PGAM5 as a Mammalian Protein Histidine Phosphatase that Plays a Central Role to Negatively Regulate CD4(+) T Cells.
abstract: Whereas phosphorylation of serine, threonine, and tyrosine is exceedingly well characterized, the role of histidine phosphorylation in mammalian signaling is largely unexplored. Here we show that phosphoglycerate mutase family 5 (PGAM5) functions as a phosphohistidine phosphatase that specifically associates with and dephosphorylates the catalytic histidine on nucleoside diphosphate kinase B (NDPK-B). By dephosphorylating NDPK-B, PGAM5 negatively regulates CD4(+) T cells by inhibiting NDPK-B-mediated histidine phosphorylation and activation of the K(+) channel KCa3.1, which is required for TCR-stimulated Ca(2+) influx and cytokine production. Using recently developed monoclonal antibodies that specifically recognize phosphorylation of nitrogens at the N1 (1-pHis) or N3 (3-pHis) positions of the imidazole ring, we detect for the first time phosphoisoform-specific regulation of histidine-phosphorylated proteins in vivo, and we link these modifications to TCR signaling. These results represent an important step forward in studying the role of histidine phosphorylation in mammalian biology and disease.
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10016, USA; The Helen L. and Martin S. Kimmel Center for Biology and Medicine, New York University Langone Medical Center, New York, NY 10016, USA; Skirball Institute for Biomolecular Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Saswati
authors.initials: S
authors.lastname: Panda
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10016, USA; The Helen L. and Martin S. Kimmel Center for Biology and Medicine, New York University Langone Medical Center, New York, NY 10016, USA; Skirball Institute for Biomolecular Medicine, New York University Langone Medical Center, New York, NY 10016, USA; Division of Nephrology, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Shekhar
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10016, USA; The Helen L. and Martin S. Kimmel Center for Biology and Medicine, New York University Langone Medical Center, New York, NY 10016, USA; Skirball Institute for Biomolecular Medicine, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Zhai
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pathology, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Vaeth
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Fuhs
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Tony
authors.initials: T
authors.lastname: Hunter
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10016, USA; The Helen L. and Martin S. Kimmel Center for Biology and Medicine, New York University Langone Medical Center, New York, NY 10016, USA; Skirball Institute for Biomolecular Medicine, New York University Langone Medical Center, New York, NY 10016, USA; Division of Nephrology, New York University Langone Medical Center, New York, NY 10016, USA. Electronic address: edward.skolnik@nyumc.org.
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Skolnik
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D020013:Calcium Signaling; D016207:Cytokines / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D006086:Graft vs Host Disease / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D057809:HEK293 Cells; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006639:Histidine; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009701:Nucleoside-Diphosphate Kinase / Q000378:metabolism; D010641:Phenotype; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; C496925:Kcnn4 protein, mouse; D024101:Mitochondrial Proteins; D011948:Receptors, Antigen, T-Cell; D006639:Histidine; D009701:Nucleoside-Diphosphate Kinase; C542596:NDPK-B protein, human; C529563:PGAM5 protein, human; C570696:PGAM5 protein, mouse; D010749:Phosphoprotein Phosphatases
keywords: PGAM5; T cell activation; histidine phosphorylation; protein histidine phosphatases