Phosphatase PPM1A Dictates The Sensing Of Cytosolic RNA

Cytosolic RNA sensing is a prerequisite for initiation of innate immune response against RNA viral pathogens. Signaling through RIG-like receptors to TBK1/IKKε kinases is transduced by mitochondrial-associated MAVS. However, the precise mechanism underlying MAVS-mediated TBK1/IKKε activation remains obscure. Here we reported that metal ion-dependent phosphatase 1A (PPM1A), depending on its catalytic ability, dampened the RLR-IRF3 axis to silence cytosolic RNA sensing signaling. In accordance, Ppmla-/- mice resisted to RNA virus attack, while transgenic zebrafish expressing PPM1A displayed profoundly increased RNA virus vulnerability. Human Ppmla-/- cell line and mouse Ppmla-/- macrophages also exhibited robustly enhanced antiviral responses. By using combinatorial approached of mass-spectrometry, cell biological and biochemical methods, we demonstrated that PPM1A was an inherent partner of TBK1/IKKε complex and targeted both MAVS and TBK1/IKKε for dephosphorylation. Consequently, PPM1A prevents TBKl/IKKε activation and disrupts MAVS-driven formation of signaling complex. Conversely, a high level of MAVS can dissociate the TBK1:PPM1A complex to override PPM1A-mediated inhibition. These findings identify PPM1A as the first known phosphatase of MAVS, and elucidate the physiological function of PPM1Ain antiviral immunity on whole animals.