Patterson Heide Christine, Gerbeth Carolin, Thiru Prathapan, Vögtle Nora F, Knoll Marko, Shahsafaei Aliakbar, Samocha Kaitlin E, Huang Cher X, Harden Mark Michael, Song Rui, Chen Cynthia, Kao Jennifer, Shi Jiahai, Salmon Wendy, Shaul Yoav D, Stokes Matthew P, Silva Jeffrey C, Bell George W, MacArthur Daniel G, Ruland Jürgen, Meisinger Chris, Lodish Harvey F
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;
Institute for Biochemistry and Molecular Biology and BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany;
Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):E5679-88. doi: 10.1073/pnas.1517932112. Epub 2015 Oct 5.
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.
活性氧（ROS）如过氧化氢（H2O2）通过诱导信号传导来维持细胞内稳态。H2O2通过氧化关键的半胱氨酸残基来调节磷酸酶和许多其他信号分子的活性，这导致了一种观点，即ROS信号传导的起始是广泛且非特异性的，因此与其他信号通路有着根本的区别。在此，我们报道H2O2信号传导具有常规信号转导级联的特征。它由分层信号事件控制，导致聚焦反应，因为结果表明线粒体呼吸链位于酪氨酸蛋白激酶Lyn的上游，Lyn位于酪氨酸蛋白激酶SYK（Syk）的上游，而Syk位于参与信号传导、转录、翻译、代谢和细胞周期调控的众多靶点的上游。H2O2信号传导的活性介质共定位，因为H2O2诱导线粒体相关的Lyn和Syk磷酸化，并且有一批Lyn和Syk存在于线粒体内膜间隙中。最后，相同的中介物控制对H2O2有反应的组织和物种中的信号反应，因为呼吸链、Lyn和Syk在小鼠B细胞、成纤维细胞和鸡DT40 B细胞的H2O2信号传导中同样是必需的。与广泛的作用一致，Syk途径在各组织中共同表达，起源于早期后生动物，并且在人类中显示出进化限制的证据。这些结果表明，H2O2信号传导受一个信号转导途径的控制，该途径将呼吸链与造血和非造血细胞中线粒体内膜间隙定位的、普遍存在且古老的Syk途径联系起来。
