Cell autonomous inflammation in VEXAS is mediated by cGAS-STING

  • bioRxiv. 2026 May 29:2026.05.26.727520. doi: 10.64898/2026.05.26.727520.
Samuel J Magaziner  1 ,  Jason C Collins  2 ,  Brecca Miller  1  3  4 ,  Patrick Zheng  2 ,  Amy K Wang  1 ,  Jerome Hadjadj  1  5 ,  Juan Carlos Baladrán  6 ,  Maria Sirenko  1  6 ,  Maya English  2 ,  James Bertlin  2  7 ,  Rebecca Murray  8  9  10 ,  Peter H Whitney  3 ,  Tania J González-Robles  3  4 ,  Deborah Rivera  1 ,  Yan Wang  11 ,  Duy T Tran  12 ,  Zulfeqhar A Syed  13 ,  Valentina Baena  13 ,  Timothee Lionnet  3  14  15 ,  Kelly V Ruggles  3  4 ,  Iannis Aifantis  6 ,  Dan A Landau  8  9  10 ,  Achim Werner  2 ,  David B Beck  1  16  17
Affiliations
  • 1. Center for Human Genetics and Genomics, NYU Grossman School of Medicine, New York, NY, USA.
  • 2. Stem Cell Biochemistry Section, NIDCR, National Institutes of Health, Bethesda, MD, USA.
  • 3. Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY, USA.
  • 4. Division of Precision Medicine, Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA.
  • 5. Sorbonne Universite, Service de Medecine Interne, Hopital Saint Antoine, AP-HP, Paris, France.
  • 6. Department of Pathology and Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA.
  • 7. School of Clinical Medicine, University of Cambridge, Cambridge, UK.
  • 8. Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA.
  • 9. New York Genome Center, New York, NY, USA.
  • 10. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • 11. Mass Spectrometry Facility, NIDCR, National Institutes of Health, Bethesda, MD, USA.
  • 12. NIDCR Imaging Core, NIDCR, National Institutes of Health, Bethesda, MD, USA.
  • 13. Electron Microscopy Core, NHLBI, National Institutes of Health, Bethesda, MD, USA.
  • 14. Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, USA.
  • 15. Department of Biomedical Engineering, NYU Tandon School of Engineering, Brooklyn, NY, USA.
  • 16. Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, New York, NY, USA.
  • 17. Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA.
PMID: 42244578 DOI: 10.64898/2026.05.26.727520
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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