HSV Infection Induces Production of ROS, which Potentiate Signaling from Pattern Recognition Receptors: Role for S-glutathionylation of TRAF3 and 6

PLoS Pathogens

Hidenori Ichijo¹  Kristy A. Horan²  Stine H. Rahbek²  Regina Gonzalez-Dosal²  Søren R. Paludan³  Zhijian J. Chen⁴  John J. Mieyal⁵  Rune Hartmann⁶ 

[1] Center of Excellence Program, Japan Science and Technology Corporation, The University of Tokyo, Tokyo, Japan;Department of Biomedicine, Aarhus University, Aarhus, Denmark;Department of Molecular Biology, Aarhus University, Aarhus, Denmark;Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America;Department of Pharmacology, Case Western Reserve University, School of Medicine, Cleveland, Ohio, United States of America;The Louis B. Stokes Veterans Affairs Medical Research Center, Cleveland, Ohio, United States of America

关键词: Redox signaling;    Immune response;    Macrophages;    Transcription factors;    Herpes simplex virus;    Immune receptor signaling;    Cytokines;    Reactive oxygen species;   

DOI  :  10.1371/journal.ppat.1002250

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

The innate immune response constitutes the first line of defense against infections. Pattern recognition receptors recognize pathogen structures and trigger intracellular signaling pathways leading to cytokine and chemokine expression. Reactive oxygen species (ROS) are emerging as an important regulator of some of these pathways. ROS directly interact with signaling components or induce other post-translational modifications such as S-glutathionylation, thereby altering target function. Applying live microscopy, we have demonstrated that herpes simplex virus (HSV) infection induces early production of ROS that are required for the activation of NF-κB and IRF-3 pathways and the production of type I IFNs and ISGs. All the known receptors involved in the recognition of HSV were shown to be dependent on the cellular redox levels for successful signaling. In addition, we provide biochemical evidence suggesting S-glutathionylation of TRAF family proteins to be important. In particular, by performing mutational studies we show that S-glutathionylation of a conserved cysteine residue of TRAF3 and TRAF6 is important for ROS-dependent activation of innate immune pathways. In conclusion, these findings demonstrate that ROS are essential for effective activation of signaling pathways leading to a successful innate immune response against HSV infection.

【 授权许可】

CC BY