Taking the “STING” out of immune dysfunction
The detection of pathogen-derived nucleic acids is a central strategy by which the host senses infection and initiates protective immune responses. Cyclic GMP-AMP synthase (cGAS) is a dsDNA sensor. It catalyzes the synthesis of cyclic GMP-AMP (cGAMP), which stimulates the induction of type I interferons through the STING–TBK1–IRF-3 signaling axis. However, the precise mechanisms that govern activation of STING by cGAMP and subsequent activation of TBK1 remain unclear. A paper published by Dr. Pingwei Li’s lab in this week’s issue of Nature show that a conserved PLPLRT/SD motif mediates the recruitment and activation of TBK1. Crystal structures of TBK1 bound to STING reveal that the PLPLRT/SD motif binds to the dimer interface of TBK1. Moreover, this study shows that full-length STING oligomerizes after it binds cGAMP, which is essential for the activation of STING-mediated signaling. These findings provide a structural basis for the development of STING agonists and antagonists for the treatment of cancer and autoimmune disorders.