Cell autonomous inflammation in VEXAS is mediated by cGAS-STING.

Area of Science:

• Immunology
• Genetics
• Cell Biology

Background:

• VEXAS is a severe adult-onset autoinflammatory disease.
• It stems from somatic mutations affecting UBA1, the key enzyme in ubiquitylation.
• The mechanism driving myeloid cell activation in VEXAS remains unclear.

Purpose of the Study:

• To elucidate how reduced cytoplasmic UBA1 activity triggers cell-intrinsic immune responses in VEXAS.
• To identify the molecular pathways linking UBA1 dysfunction to inflammation.

Main Methods:

• Multi-omic analyses
• Biochemical assays
• Cell biological studies
• Utilized model systems and patient-derived cells

Main Results:

• Loss of cytoplasmic UBA1 disrupts ER-associated degradation (ERAD) and mitochondrial homeostasis.
• ERAD failure leads to STING accumulation and hallmark VEXAS features like vacuoles.
• Mitochondrial dysfunction causes mtDNA leakage, activating cGAS-STING signaling and cytokine production.

Conclusions:

• The cGAS-STING pathway is a critical driver of inflammation in VEXAS.
• STING inhibition or preventing mtDNA leakage can resolve inflammation in VEXAS models and patient cells.
• This highlights the cGAS-STING pathway as a therapeutic target for VEXAS.