Adaptation to ER-stress via serine glycine metabolism licences STING signalling and CMV control in intestinal epithelial cells

Mucosal cytomegalovirus (CMV) infection represents a leading cause for complicated disease behaviour and proctocolectomy in patients with inflammatory bowel disease (IBD). Using a genetic loss-of-function mouse model of the hypomorphic IBD risk gene X-box-binding protein 1 (XBP1), isotope-assisted metabolomics and pharmacologic approaches, we unravel the molecular control of gut epithelial STING signalling by unresolved endoplasmic reticulum (ER) stress. We demonstrate that unresolved epithelial ER stress, evoked by Xbp1 deficiency, leads to exhausted STING signalling and an impaired ability to control CMV infection, which is driven by the generation of reactive oxygen species (ROS). ROS generation is controlled by cellular glycine influx and de-novo serin synthesis enabling glutathione production, which can be pharmacologically exploited to restrore STING signaling. Pharmacological scavenging of ROS with N-acetly cysteine restores epithelial STING signalling and limits CMV infection in IECs. Our findings unravel the serine-glycine dependent metabolic control by ER stress that licences STING signaling and susceptibility to infection in gut epithelium. ### Competing Interest Statement The authors have declared no competing interest.