Scientists Identify Key Drug Target Required to Activate Nuclear Factor Kappa B in Specialized Protein Complex

Nuclear factor κB (NF-κB) plays an important role in the occurrence of various human diseases. Various inflammatory signals, including circulating lipopolysaccharides (LPSs), can activate the expression of NF-κB through special receptors. Recently, in a research report titled "Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB" published in the international journal Cell, scientists from Dana-Farber Cancer Institute and other institutions are expected to help develop new targeted therapies to inhibit the activation of NF-κB.

Researchers said that NF-κB is a transcription factor that plays an important role in various autoimmune diseases, inflammatory diseases and cancers in humans. In this study, researchers tracked the activation mechanism of NF-κB and identified a key susceptibility site. NF-κB can be activated by circulating lipopolysaccharide that binds to the cell surface receptor TLR4. After conducting studies using CRISPR/Cas9, researchers found that this LPS receptor TLR4 depends on OST-A to function properly. OST-A is an oligosaccharide transferase complex, and the OST complex can be inhibited by a compound called NGI-1. However, researchers are currently unclear about the molecular mechanism behind its effect.

Figure 1. Identification of genes required for NF-κB pathway activity in response to various stimuli. (Lampson, Benjamin L., et al. 2024)

After conducting CRISPR screening and studying using cryo-electron microscopy, the researchers found that NGI-1 can bind to OST-A on the catalytic subunit STT3A of the complex. There, NGI-1 drives the complex into an inactive state and prevents TLR4 from reaching the cell surface, thus preventing NF-κB activation. The development of agents that inhibit STT3A may represent a new potential strategy to block NF-κB activation in response to LPS. NF-κB is often involved in a range of human diseases including autoimmune diseases, inflammatory diseases and cancer. This may indicate that this method has broad practicality.

In summary, the results of this article provide basic principles and preliminary steps for the development of STT3A-specific inhibitors. The potential of simultaneous base-based editor and structural studies in defining drug mechanisms of action is also elucidated.

Reference

Lampson, Benjamin L., et al. "Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB." Cell 187.9 (2024): 2209-2223.