PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1
| العنوان: | PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1 |
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| المؤلفون: | Fansen Meng, Jian Zou, Weiwen Xiang, Pinglong Xu, Tao Shen, Zongping Xia, Shiying Wu, Yunyun Fan, Xin-Hua Feng, Mu Xiao, Qian Zhang, Yao Zhou, Xia Lin |
| المصدر: | Science Advances |
| بيانات النشر: | American Association for the Advancement of Science, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Embryo, Nonmammalian, TBK1, cytosolic RNA sensing, IκB kinase, Sendai virus, Animals, Genetically Modified, Mice, Cytosol, TANK-binding kinase 1, RNA interference, RNA, Small Interfering, health care economics and organizations, Research Articles, Zebrafish, Mice, Knockout, Multidisciplinary, biology, SciAdv r-articles, MAVS, humanities, Cell biology, PPM1A, I-kappa B Kinase, Protein Phosphatase 2C, Models, Animal, RNA Interference, Research Article, Protein Serine-Threonine Kinases, behavioral disciplines and activities, phosphatase, Cell Line, 03 medical and health sciences, health services administration, Virology, Animals, Humans, Mitochondrial antiviral-signaling protein, Adaptor Proteins, Signal Transducing, Innate immune system, RNA, RNA virus, social sciences, Vesiculovirus, biology.organism_classification, Mice, Inbred C57BL, 030104 developmental biology, HEK293 Cells, Interferon Regulatory Factor-3, CRISPR-Cas Systems, Interferon regulatory factors, antiviral host defense |
| الوصف: | An enzyme safeguards antiviral recognition machinery to avoid leaking and excessive danger response. Cytosolic RNA sensing is a prerequisite for initiation of innate immune response against RNA viral pathogens. Signaling through RIG-I (retinoic acid–inducible gene I)–like receptors (RLRs) to TBK1 (Tank-binding kinase 1)/IKKε (IκB kinase ε) kinases is transduced by mitochondria-associated MAVS (mitochondrial antiviral signaling protein). However, the precise mechanism of how MAVS-mediated TBK1/IKKε activation is strictly controlled still remains obscure. We reported that protein phosphatase magnesium-dependent 1A (PPM1A; also known as PP2Cα), depending on its catalytic ability, dampened the RLR-IRF3 (interferon regulatory factor 3) axis to silence cytosolic RNA sensing signaling. We demonstrated that PPM1A was an inherent partner of the TBK1/IKKε complex, targeted both MAVS and TBK1/IKKε for dephosphorylation, and thus disrupted MAVS-driven formation of signaling complex. Conversely, a high level of MAVS can dissociate the TBK1/PPM1A complex to override PPM1A-mediated inhibition. Loss of PPM1A through gene ablation in human embryonic kidney 293 cells and mouse primary macrophages enabled robustly enhanced antiviral responses. Consequently, Ppm1a−/− mice resisted to RNA virus attack, and transgenic zebrafish expressing PPM1A displayed profoundly increased RNA virus vulnerability. These findings identify PPM1A as the first known phosphatase of MAVS and elucidate the physiological function of PPM1A in antiviral immunity on whole animals. |
| اللغة: | English |
| تدمد: | 2375-2548 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::18fd50b556cd5688b14e5ff228d261f3Test http://europepmc.org/articles/PMC4942338Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....18fd50b556cd5688b14e5ff228d261f3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23752548 |
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