Preprint identifies cGAS-STING pathway as driver of cell-intrinsic inflammation in VEXAS syndrome

A preprint posted to bioRxiv presents mechanistic evidence that the cGAS-STING innate immune signalling pathway mediates cell-autonomous inflammation in VEXAS syndrome — a severe adult-onset inflammatory disease caused by somatic mutations in the UBA1 gene.

VEXAS (an acronym for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) was first described in 2020 and is caused by acquired somatic mutations — arising during a person's lifetime rather than being inherited — that reduce the cytoplasmic activity of UBA1, the primary initiating enzyme for the ubiquitylation pathway. How this hypomorphic state drives immune activation in mature myeloid cells has remained unclear.

Using unbiased multi-omic, biochemical, and cell biological analyses in model systems and patient-derived cells, the authors report that loss of cytoplasmic UBA1 activity convergently disrupts endoplasmic reticulum-associated degradation (ERAD) and mitochondrial homeostasis. These disruptions appear to culminate in activation of the cGAS-STING pathway, a DNA-sensing innate immune circuit increasingly recognised as a driver of sterile inflammation in a range of diseases.

The findings, which have not yet undergone peer review, suggest cGAS-STING inhibition as a potential mechanistic target for therapeutic investigation in VEXAS. As a rare disease caused by somatic rather than germline mutation, VEXAS sits at the intersection of haematology, rheumatology, and clinical genetics; the preprint is likely to be of interest to researchers working across these fields.