151. The deubiquitinase CYLD is a specific checkpoint of the STING antiviral signaling pathway
- Author
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Ze Hong, Heng Liu, Lele Zhang, Xing Liu, Juanjuan Zhu, Ning Wei, Ye Cui, Chen Wang, Senlin Li, Wei Meng, Zhengjun Chen, Yanni Cai, Huansha Yu, Qiang Wang, and Quanyi Wang
- Subjects
0301 basic medicine ,Small interfering RNA ,Golgi Apparatus ,Herpesvirus 1, Human ,Pathology and Laboratory Medicine ,Biochemistry ,Deubiquitinating enzyme ,Mice ,0302 clinical medicine ,Ubiquitin ,Medicine and Health Sciences ,Small interfering RNAs ,Post-Translational Modification ,Phosphorylation ,Polyubiquitin ,lcsh:QH301-705.5 ,Mice, Knockout ,biology ,Precipitation Techniques ,Deubiquitinating Enzyme CYLD ,Cell biology ,Nucleic acids ,Cysteine Endopeptidases ,Medical Microbiology ,Viral Pathogens ,030220 oncology & carcinogenesis ,Stimulator of interferon genes ,Viruses ,Herpes Simplex Virus-1 ,Pathogens ,Signal transduction ,Research Article ,Signal Transduction ,lcsh:Immunologic diseases. Allergy ,Herpesviruses ,Immunoblotting ,Immunology ,Molecular Probe Techniques ,macromolecular substances ,Research and Analysis Methods ,Transfection ,Antiviral Agents ,Microbiology ,03 medical and health sciences ,Virology ,Genetics ,Immunoprecipitation ,Animals ,Humans ,Molecular Biology Techniques ,Non-coding RNA ,Microbial Pathogens ,Molecular Biology ,Innate immune system ,HEK 293 cells ,Organisms ,Ubiquitination ,Biology and Life Sciences ,Proteins ,Membrane Proteins ,Immunity, Innate ,eye diseases ,Gene regulation ,Herpes Simplex Virus ,Mice, Inbred C57BL ,Sting ,HEK293 Cells ,030104 developmental biology ,lcsh:Biology (General) ,biology.protein ,RNA ,Parasitology ,Gene expression ,Interferons ,DNA viruses ,lcsh:RC581-607 ,HeLa Cells - Abstract
Stimulator of interferon genes (STING) is critical for cytosolic DNA-triggered innate immunity. STING is modified by several types of polyubiquitin chains. Here, we report that the deubiquitinase CYLD sustains STING signaling by stabilizing the STING protein. CYLD deficiency promoted the K48-linked polyubiquitination and degradation of STING, attenuating the induction of IRF3-responsive genes after HSV-1 infection or the transfection of DNA ligands. Additionally, CYLD knockout mice were more susceptible to HSV-1 infection than their wild-type (WT) littermates. Mechanistically, STING translocated from the ER to the Golgi upon HSV-1 stimulation; CYLD partially accumulated with STING and interacted selectively with K48-linked polyubiquitin chains on STING, specifically removing the K48-linked polyubiquitin chains from STING and ultimately boosting the innate antiviral response. Our study reveals that CYLD is a novel checkpoint in the cGAS-STING signaling pathway and sheds new light on the dynamic regulation of STING activity by ubiquitination., Author summary STING is critical for mediating the production of type I interferons and other proinflammatory cytokines. The appropriate activation of STING signaling is precisely modulated to maintain immune homeostasis. It is well established that covalent modification of STING by different types of polyubiquitin chains serves to fine-tune STING activity in response to extracellular and intracellular stresses. However, it remains poorly understood how these polyubiquitin chains on STING are dynamically removed in response to different stimuli. In this study, we characterized the deubiquitinase CYLD, which partially accumulates with STING upon HSV-1 infection and interacts selectively with the K48-linked polyubiquitin chains on STING. CYLD specifically removes K48-linked polyubiquitin chains from STING and thus promotes antiviral responses. Our study reveals a novel function of CYLD in the STING signaling pathway and indicates that CYLD is an important target for modulating the host response to infections caused by DNA pathogens.
- Published
- 2018