Sting orchestrates the crosstalk between polyunsaturated fatty acids metabolism and inflammatory responses
Vila I.K. et al. (BioRxiv) DOI: 10.1101/2020.12.22.423950
regulation of inflammatory response
The authors present observations supporting a model of cGAS/STING: polyunsaturated fatty acid (PUFA) cross-regulation under different conditions, including homeostasis, thermogenesis, and inflammation. Using STING knockout mice, the authors show global metabolic changes, including improved insulin-independent glucose management, decreased hepatic gluconeogenesis, and upregulation of genes associated with adipocyte differentiation and browning (Ucp-1, PGC1a). The authors argue this program is largely driven by white adipocytes (not brown adipocytes or myeloid cells) and found an accumulation of Omega 3 fatty acids during metabolomics profiling of STING knockout mice.
The authors went on to study the binding partners of STING and found that Fatty acid desaturase 2 (FADS2) is a previously unidentified binding partner of STING and negatively regulates its’ activity during steady state and thermogenesis. During inflammation, they found that STING negatively regulates FADS2 metabolism in the context of dsDNA transfection and TREX1 knockout in both HEK293Ts and mouse embryonic fibroblasts. Knockdown of FADS2 also conferred protection against viral infection with HSV-1, further supporting its’ role as a negative regulator of STING and cell entry into the anti-viral state.
Importantly, the authors found through in silico modelling that ligands of STING (e.g. cGAMP, DMXAA) bind to FADS2 and vice versa (e.g. PUFAs), which was validated for cGAMP and FADS2 by co-IP and Western blot.
The authors found a clear relationship between STING and FADS2 and began to highlight some of this cross-regulation, but a lot of questions remain about the determinants of how STING and FADS2 influence one another. The in silico observations showed that ligands of cGAS/STING bind FADS2 and vice versa, but what determines when a ligand (cGAMP, PUFA, or other) stimulates one pathway vs. another? Are there allosteric binding partners that stimulate signal transduction of one pathway vs. another? Many of these questions remain to be explored.
Additionally, the authors interrogate this relationship largely in adipocytes, fibroblasts, or generally cells of mesodermal origin. While the role of this cross-regulation was examined in myeloid cells to assess the drivers of the metabolic phenotype the authors observed, the role of this regulatory mechanism in immune cells during steady state and inflammation, which have this same machinery (namely cGAS/STING and PUFA), remains to be seen.
This paper highlights a novel interaction between cGAS/STING and FADS2, characterizing a previously unexplored regulatory axis in adipocytes. This could have implications for non-immune participation in forming the immune microenvironmental niche in various settings and regulation of these same pathways both in immune and non-immune cells. Further characterization of the ligand-enzyme interactions and what regulates them may illuminate the functional implications of these pathways in disease and present new targets for immunotherapy.
Overall, this paper highlights an interesting, context-dependent regulatory mechanism of inflammation through several orthogonal experimental approaches and provides a great jumping-off point for further characterization.
Reviewed by Natalie Vaninov as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford. Follow her on Twitter.