A team of researchers has proposed a new model for how glucocorticoid receptor (GR) protein interacts with the NF-kB signaling pathway in order to control inflammatory response. The standing model suggests that GR binds directly to NF-kB itself in a DNA binding-independent manner, however, this new study found that GR can bind one at a time to some of the same pieces of DNA that NF-kB interacts with. The study was published in Nature Communications.
Glucocorticoids (GCs), such as dexamethasone, are synthetic glucocorticoid hormones commonly used to treat inflammatory conditions such as autoimmune disorders, asthma, and cancer. They work by binding the GR protein and are effective as an anti-inflammatory but come with severe side effects such as skin atrophy, glaucoma, and insulin resistance. An ongoing body of research aims to separate the benefits from the problematic side effects.
GR can bind DNA in two different ways, resulting in some genes being turned on and some turned off. The side effects from GR-targeting drugs are thought to be the result of activating metabolism and bone growth-related genes and the anti-inflammatory effects are believed to be from deactivating inflammatory-related genes. The paper describes that GR binds DNA differently than previously believed and the data shows that it competes with NF-kB to bind to the same stretches of DNA. Using X-ray crystallography and NMR, the research team showed that GR binds DNA one at a time in between the two areas that are contacted by NF-kB.
"This type of interaction, where GR is acting one at a time - we think it's druggable," says co-author Ortlund, who is associate professor of biochemistry at Emory University School of Medicine.
The findings suggest that several studies of inflammatory gene regulation should be reinterpreted since GR was previously believed to interact with NFkB sites by “tethering” via protein-protein interactions.
Image: GR binding to kBRE site in IL8 promoter. Image courtesy of Hudson et al Nature Communications 2018.