Fig. 4

STING trafficking route and its relationship with autophagy. STING activation requires its translocation from ER to the Golgi apparatus, which resembles the early secretory pathway. In a steady state, STING is sequestered on ER membrane by STIM1 and interacts with the translocon complex, PERK, and STX17. STEEP regulated STING exit by promoting COPII assembly and recruiting VPS34 to augment phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature. There are three models depicting the relationship between STING and autophagy. a In model 1, cGAS can induce canonical autophagy, which parallels and negatively regulates STING trafficking. TBK1 can activate the STING–IRF3 axis and induced P65-mediated STING degradation via double-membrane autophagosomes, which eventually fuse with a lysosome. Several autophagy receptors like CCDC50, UXT, and NPC1 mediate STING degradation. b In model 2, STING can induce canonical autophagosome formation using ERGIC membrane souce, dependent on both WIPIs and ATG5. This process facilitates the cytosolic clearance of the virus and dsDNA. c In model 3, STING activation recruits the V-ATPase–ALG16L1 axis to mediate LC3B lipidation of the single-membrane bacteria-containing vacuole. V-ATPase can sense the damage of the endoplasmic reticulum-Golgi intermediate compartment/Golgi membranes and bind to the ATG16L1 WD40 domain. SopF, a bacterial effector protein, can co-act with ARF1 and inhibit the process by ADP-ribosylating Gln124 of ATP6V0C. ARF: ADP-ribosylation factor; ATG, autophagy-related 1; BECN1, beclin 1; BD, (ATG5) binding domain; CCDC50 coiled-coil domain containing 50; cGAMP cyclic GMP–AMP; cGAS cyclic GMP–AMP synthase; COP coat protein complex, ER endoplasmic reticulum, ERGIC ER–Golgi intermediate compartments, IRF3 interferon regulatory factor 3, LC3 microtubule-associated protein 1 light chain 3, NPC1 NPC intracellular cholesterol transporter 1, Orai1 ORAI calcium release-activated calcium modulator 1, PE phosphatidylethanolamine, PERK PKR-like endoplasmic reticulum kinase, PI3K phosphoinositide 3-kinase, PtdIns(3)P phosphatidylinositol-3-phosphate, STEEP STING ER exit protein, STIM1 stromal interaction molecule 1, STING stimulator of interferon genes, STX17 syntaxin 17, TBK1 TANK-binding kinase 1, TOLLIP Toll-interacting protein, TRAPβ translocon-associated protein subunit beta, ULK1 Unc-51 like autophagy activating kinase 1, UXT ubiquitously expressed prefoldin like chaperone, VPS34 vacuolar protein sorting 34, WIPI WD-repeat protein interacting with phosphoinositides, WIR WIPI2 interacting region