RRC ID 67563
Author Patterson HC, Gerbeth C, Thiru P, Vögtle NF, Knoll M, Shahsafaei A, Samocha KE, Huang CX, Harden MM, Song R, Chen C, Kao J, Shi J, Salmon W, Shaul YD, Stokes MP, Silva JC, Bell GW, MacArthur DG, Ruland J, Meisinger C, Lodish HF.
Title A respiratory chain controlled signal transduction cascade in the mitochondrial intermembrane space mediates hydrogen peroxide signaling.
Journal Proc Natl Acad Sci U S A
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.
Volume 112(42)
Pages E5679-88
Published 2015-10-20
DOI 10.1073/pnas.1517932112
PII 1517932112
PMID 26438848
PMC PMC4620870
MeSH Animals Cells, Cultured Chickens Electron Transport* Enzyme Activation Hydrogen Peroxide / metabolism* Intracellular Signaling Peptides and Proteins / metabolism Mice Mitochondrial Membranes / metabolism* Phosphorylation Protein-Tyrosine Kinases / metabolism Reactive Oxygen Species / metabolism Signal Transduction* Syk Kinase Tyrosine / metabolism
IF 9.412
Human and Animal Cells DT40(RCB1464)