PPM1A regulates antiviral signaling by antagonizing TBK1-mediated STING phosphorylation and aggregation

PLoS Pathog. 2015 Mar 27;11(3):e1004783. doi: 10.1371/journal.ppat.1004783. eCollection 2015 Mar.

Abstract

Stimulator of interferon genes (STING, also known as MITA and ERIS) is critical in protecting the host against DNA pathogen invasion. However, the molecular mechanism underlying the regulation of STING remains unclear. Here, we show that PPM1A negatively regulates antiviral signaling by targeting STING in its phosphatase activity-dependent manner, and in a line with this, PPM1A catalytically dephosphorylates STING and TBK1 in vitro. Importantly, we provide evidence that whereas TBK1 promotes STING aggregation in a phosphorylation-dependent manner, PPM1A antagonizes STING aggregation by dephosphorylating both STING and TBK1, emphasizing that phosphorylation is crucial for the efficient activation of STING. Our findings demonstrate a novel regulatory circuit in which STING and TBK1 reciprocally regulate each other to enable efficient antiviral signaling activation, and PPM1A dephosphorylates STING and TBK1, thereby balancing this antiviral signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chlorocebus aethiops
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Mice
  • Mice, Knockout
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / immunology*
  • Phosphorylation / genetics
  • Phosphorylation / immunology
  • Protein Phosphatase 2C
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / immunology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Vero Cells

Substances

  • Membrane Proteins
  • STING protein, human
  • Sting1 protein, mouse
  • Tbk1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • PPM1A protein, human
  • Phosphoprotein Phosphatases
  • Ppm1a protein, mouse
  • Protein Phosphatase 2C