ArfGAP2 deficiency ameliorates autoinflammation by regulating STING signaling and proton channel activity

• ArfGAP2 is identified as a critical modulator of STING signaling and proton channel activity, offering a novel therapeutic target for SAVI. • Genetic ablation of ArfGAP2 attenuates STING-mediated ISG induction and NF-κB-dependent proinflammatory cytokine secretion. • ArfGAP2 deficiency impairs STING-mediated Golgi deacidification, leading to altered cargo trafficking and cell surface proteome. • The study provides evidence that SAVI pathology may be driven by STING's proton channel activity independent of IFN signaling, challenging current paradigms.