PUBLICATION
PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1
- Authors
- Xiang, W., Zhang, Q., Lin, X., Wu, S., Zhou, Y., Meng, F., Fan, Y., Shen, T., Xiao, M., Xia, Z., Zou, J., Feng, X.H., Xu, P.
- ID
- ZDB-PUB-160716-4
- Date
- 2016
- Source
- Science advances 2: e1501889 (Journal)
- Registered Authors
- Zou, Jian
- Keywords
- MAVS, PPM1A, TBK1, antiviral host defense, cytosolic RNA sensing, phosphatase
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism*
- Animals
- Animals, Genetically Modified/metabolism
- CRISPR-Cas Systems/genetics
- Cell Line
- Cytosol/metabolism*
- Embryo, Nonmammalian/metabolism
- Embryo, Nonmammalian/virology
- HEK293 Cells
- Humans
- I-kappa B Kinase/metabolism
- Interferon Regulatory Factor-3/genetics
- Interferon Regulatory Factor-3/metabolism
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Models, Animal
- Protein Phosphatase 2C/antagonists & inhibitors
- Protein Phosphatase 2C/genetics*
- Protein Phosphatase 2C/metabolism
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism*
- RNA/metabolism*
- RNA Interference
- RNA, Small Interfering/metabolism
- Sendai virus/drug effects
- Sendai virus/pathogenicity
- Sendai virus/physiology
- Vesiculovirus/drug effects
- Vesiculovirus/pathogenicity
- Vesiculovirus/physiology
- Zebrafish/growth & development
- Zebrafish/metabolism
- PubMed
- 27419230 Full text @ Sci Adv
Citation
Xiang, W., Zhang, Q., Lin, X., Wu, S., Zhou, Y., Meng, F., Fan, Y., Shen, T., Xiao, M., Xia, Z., Zou, J., Feng, X.H., Xu, P. (2016) PPM1A silences cytosolic RNA sensing and antiviral defense through direct dephosphorylation of MAVS and TBK1. Science advances. 2:e1501889.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping