This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility:


peer-reviewed publication

trusted source


Study uncovers drug target in a protein complex required for activation of NF-κB

DNA, which has a double-helix structure, can have many genetic mutations and variations. Credit: NIH

A new paper by Dana-Farber Cancer Institute scientists lays the foundation for targeted therapies to inhibit the 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 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.

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, , and cancers suggests that this approach could have broad utility.

The findings are published in the journal Cell.

More information: Benjamin L. Lampson et al, Positive selection CRISPR screens reveal a druggable pocket in an oligosaccharyltransferase required for inflammatory signaling to NF-κB, Cell (2024). DOI: 10.1016/j.cell.2024.03.022

Journal information: Cell
Citation: Study uncovers drug target in a protein complex required for activation of NF-κB (2024, April 25) retrieved 15 June 2024 from
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.

Explore further

Regulatory mechanism that keeps the immune system in check identified


Feedback to editors