Cell autonomous inflammation in VEXAS is mediated by cGAS-STING
Magaziner, S. J.; Collins, J. C.; Miller, B.; Zheng, P.; Wang, A. K.; Hadjadj, J.; Balandran, J. C.; Sirenko, M.; English, M.; Bertlin, J. A. C.; Murray, R.; Whitney, P. H.; Gonzalez Robles, T. J.; Rivera, D.; Wang, Y.; Tran, D. T.; Syed, Z.; Baena, V.; Lionnet, T.; Ruggles, K. J.; Aifantis, I.; Landau, D. A.; Werner, A.; Beck, D.
Show abstract
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a severe adult-onset inflammatory disease caused by somatic mutations that reduce cytoplasmic activity of UBA1, the primary initiating enzyme for ubiquitylation. How this hypomorphic state drives cell-intrinsic immune activation in mature myeloid cells is unknown. Using unbiased multi-omic, biochemical, and cell biological analyses of model systems and patient-derived cells, we show that loss of cytoplasmic UBA1 activity convergently disrupts endoplasmic reticulum- associated degradation (ERAD) and mitochondrial homeostasis. ERAD failure arises from preferential under-charging of ERAD E2 enzymes, explaining hallmark VEXAS features, including ER-derived vacuoles and unfolded protein response activation, and promotes accumulation of the ERAD substrate STING. Simultaneously, mitochondrial dysfunction drives cytosolic leakage of mitochondrial DNA, inducing cGAS-dependent STING signaling and inflammatory cytokine production. STING inhibition or reversal of mitochondrial DNA leakage resolves multi-cytokine inflammation in VEXAS models and patient myeloid cells, establishing the cGAS-STING pathway as a therapeutically actionable vulnerability.
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