title: A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling.
abstract: Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) govern cellular homeostasis by inducing signaling. H2O2 modulates the activity of phosphatases and many other signaling molecules through oxidation of critical cysteine residues, which led to the notion that initiation of ROS signaling is broad and nonspecific, and thus fundamentally distinct from other signaling pathways. Here, we report that H2O2 signaling bears hallmarks of a regular signal transduction cascade. It is controlled by hierarchical signaling events resulting in a focused response as the results place the mitochondrial respiratory chain upstream of tyrosine-protein kinase Lyn, Lyn upstream of tyrosine-protein kinase SYK (Syk), and Syk upstream of numerous targets involved in signaling, transcription, translation, metabolism, and cell cycle regulation. The active mediators of H2O2 signaling colocalize as H2O2 induces mitochondria-associated Lyn and Syk phosphorylation, and a pool of Lyn and Syk reside in the mitochondrial intermembrane space. Finally, the same intermediaries control the signaling response in tissues and species responsive to H2O2 as the respiratory chain, Lyn, and Syk were similarly required for H2O2 signaling in mouse B cells, fibroblasts, and chicken DT40 B cells. Consistent with a broad role, the Syk pathway is coexpressed across tissues, is of early metazoan origin, and displays evidence of evolutionary constraint in the human. These results suggest that H2O2 signaling is under control of a signal transduction pathway that links the respiratory chain to the mitochondrial intermembrane space-localized, ubiquitous, and ancient Syk pathway in hematopoietic and nonhematopoietic cells.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115; Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA 02139; Institut fuer Klinische Chemie und Biochemie, Klinikum rechts der Isar, 81675 Munich, Germany; ckunst@partners.org lodish@wi.mit.edu.
authors.forename: Heide Christine
authors.initials: HC
authors.lastname: Patterson
authors.affiliation: Institute for Biochemistry and Molecular Biology and BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany;
authors.forename: Carolin
authors.initials: C
authors.lastname: Gerbeth
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Prathapan
authors.initials: P
authors.lastname: Thiru
authors.affiliation: Institute for Biochemistry and Molecular Biology and BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany;
authors.forename: Nora F
authors.initials: NF
authors.lastname: Vögtle
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Marko
authors.initials: M
authors.lastname: Knoll
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115;
authors.forename: Aliakbar
authors.initials: A
authors.lastname: Shahsafaei
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114; Broad Institute, Cambridge, MA 02142;
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Samocha
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Cher X
authors.initials: CX
authors.lastname: Huang
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Mark Michael
authors.initials: MM
authors.lastname: Harden
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Rui
authors.initials: R
authors.lastname: Song
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Cynthia
authors.initials: C
authors.lastname: Chen
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kao
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Jiahai
authors.initials: J
authors.lastname: Shi
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Wendy
authors.initials: W
authors.lastname: Salmon
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Yoav D
authors.initials: YD
authors.lastname: Shaul
authors.affiliation: Cell Signaling Technology, Danvers, MA 01923;
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Stokes
authors.affiliation: Cell Signaling Technology, Danvers, MA 01923;
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Silva
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: George W
authors.initials: GW
authors.lastname: Bell
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114; Broad Institute, Cambridge, MA 02142;
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.affiliation: Institut fuer Klinische Chemie und Biochemie, Klinikum rechts der Isar, 81675 Munich, Germany;
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.affiliation: Institute for Biochemistry and Molecular Biology and BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany;
authors.forename: Chris
authors.initials: C
authors.lastname: Meisinger
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142 ckunst@partners.org lodish@wi.mit.edu.
authors.forename: Harvey F
authors.initials: HF
authors.lastname: Lodish
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002645:Chickens; D004579:Electron Transport; D004789:Enzyme Activation; D006861:Hydrogen Peroxide / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D051336:Mitochondrial Membranes / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D000072377:Syk Kinase; D014443:Tyrosine / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D014443:Tyrosine; D006861:Hydrogen Peroxide; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse
keywords: Btk; PTPN6; dasatinib; fostamatinib; rotenone