Study uncovers drug target in a protein complex required for activation of NF-κB, a transcription factor involved in multiple diseases

RESEARCH SUMMARY

Study Title:  Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB

Publication:  Cell (4/25/24)

Dana-Farber Cancer Institute authors include: William Kaelin, Jr, MD, senior author; Benjamin Lampson, MD, PhD, first author; Lixia He, PhD; Jamie Pfaff, MD; Nitin Shirole, PhD; and Yanfeng He, PhD

Summary: A new paper by Dana-Farber Cancer Institute scientists lays the foundation for targeted therapies to inhibit activation of nuclear factor kappa B (NF-κB), a transcription factor that plays a role in various autoimmune and inflammatory diseases and cancers. The study tracks the mechanism of NF-κB activation to identify a key point of vulnerability. NF-κB is activated by circulating lipopolysaccharides (LPS) that bind to the cell surface receptor TLR4. Using CRISPR/Cas9, researchers showed that this LPS receptor TLR4 depends on OST-A – an oligosaccharyltransferase complex – to function properly. OST complexes can be inhibited with a compound called NGI-1, but the molecular mechanism of its action has been unclear. By performing a CRISPR screen and cryo-electron microscopy studies, researchers found that NGI-1 binds to OST-A at the complex’s catalytic subunit, STT3A. There, NGI-1 traps the complex in an inactive state, preventing TLR4 from getting to the cell surface. This, in turn, prevents the activation of NF-κB.

Impact:  The development of agents capable of inhibiting STT3A represents a promising strategy for blocking the activation of NF-κB in response to LPS. The involvement of NF-κB in a range of autoimmune conditions, inflammatory diseases, and cancers suggests that this approach could have broad utility.

Funding: Howard Hughes Medical Institute, National Institutes of Health, Swiss National Science Foundation, Sarnoff Cardiovascular Research Foundation, Hope Funds for Cancer Research, Mr. William and Mrs. Mary Jane Rao, and Steven and Barbara Cohen.