The STING Phase-separator Suppresses Innate Immune Signaling

Liquid-liquid phase separation of soluble proteins has been studied extensively. However, neither phase separation of transmembrane protein nor cellular structure caused by phase separation has been reported. Moreover, various cubic membranes derived from organelles are found in most cells without any defined function. Here we reported the ER cubic membranes caused by STING phase separation in DNA virus-infected cells, which required STING transmembrane, IDR and dimerization domains. cGAMP or Mn2+ strongly promoted STING phase separation and maturation. STING-cubic membranes consisted of specialized ER membranes to insulate STING and TBK1 from IRF3. Enforced STING phase separation inhibited innate immunity while interfered STING droplet maturation by microtubule inhibitors enhanced immunity. STING mutants in patients with autoimmune diseases showed reduced phase separation. This STING phase separation-induced cubic membranes was named the STING Phase-separator. Our findings may shed lights on the long-sought function of cubic membranes and apply to develop new anti-viral therapies.