UBA1 dependent inflammation in VEXAS is mediated by cGAS-STING

UBA1 encodes the E1 ubiquitin-activating enzyme, which is essential for initiating the majority of ubiquitylation. VEXAS-associated mutations often specifically reduce 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 endoplasmic reticulum-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).