VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) is a genetic disease caused by somatic mutations in UBA1, resulting in severe systemic autoinflammation and hematologic manifestations. UBA1 encodes the E1 ubiquitin-activating enzyme, which is essential for initiating the majority of ubiquitylation. VEXAS-associated mutations often specifically lower cytoplasmic UBA1 activity, but how this unique hypomorphic state causes innate immune activation in mature myeloid cells is unclear. Here, using multi-omics, biochemical, and cell biological analyses of model cell lines and patient-derived samples, we identify inhibition of ER-associated degradation (ERAD) as a specific and early VEXAS signal required for initiating cellular disease hallmarks. Disrupted cytoplasmic UBA1 activity most prominently reduces ubiquitin charging of ERAD E2 enzymes, causing proteotoxic stress, ER-derived vacuoles, and activation of the unfolded protein response (UPR). Intriguingly, although UPR signaling contributes, most inflammatory pathways are driven by accumulation of the ERAD substrate and innate immune adaptor STING, which is activated by DNA accumulated in the cytoplasm of VEXAS cells. STING inhibition resolves inflammation in VEXAS model and patient monocytes. Altogether, our findings determine the molecular pathogenesis of early cell-intrinsic events driving UBA1-dependent inflammation in mature myeloid cells and nominate the STING pathway as a therapeutic target in VEXAS.