2. Academic Validation
  3. Cell autonomous inflammation in VEXAS is mediated by cGAS-STING

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

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.

Figures
Products