Researchers at the Johns Hopkins University School of Medicine have identified claudin-4 as the host protein receptor that allows the Bacteroides fragilis toxin (BFT) to enter and damage colon cells. According to a study published in Nature, this discovery explains how the toxin triggers chronic inflammation and promotes colorectal cancer, offering a new target for therapeutic decoys to block the process.
How the BFT Toxin Bypasses Colon Defenses
Bacteroides fragilis is a bacterium found in up to 20% of healthy individuals. However, specific strains produce a toxin known as BFT that can drive tumor formation. For more than 15 years, scientists knew BFT caused inflammation by cutting E-cadherin—a protein essential for the colon’s protective barrier—but they didn’t know how the toxin reached that target.
The research team, led by Dr. Cynthia Sears at the Johns Hopkins Kimmel Cancer Center, discovered that BFT does not bind directly to E-cadherin. Instead, it must first attach to claudin-4. Once this connection is made, the toxin gains access to the cell to begin its damage.
Did you know? Most protease toxins bind directly to the molecules they attack. BFT is unusual because it requires a separate receptor, claudin-4, to act as a gateway.
CRISPR Screening Identifies Claudin-4
To find the “missing link,” Maxwell White, an M.D./Ph.D. candidate in the Sears lab, conducted a genomewide CRISPR screening effort. This process involved disabling individual genes in colon epithelial cells to see which ones stopped the toxin from working.
According to White, claudin-4 emerged as a “clear, resounding top hit.” When the researchers removed claudin-4, the BFT toxin could no longer attach to the cells, leaving the E-cadherin proteins unharmed. This finding surprised the team, as Dr. Sears noted that many scientists expected the receptor to be a signaling protein, such as a G-coupled protein receptor.
Testing Molecular Decoys in Animal Models
The discovery of the claudin-4 receptor led the team to develop a molecular decoy. By creating a soluble version of claudin-4 that mimics the receptor’s binding site, researchers were able to intercept BFT before it could reach the colon wall.
In collaboration with Min Dong’s laboratory at Harvard Medical School, the team tested this strategy in mouse models. The results showed that the decoy proteins successfully protected the mice from BFT-induced colon damage. White suggests this approach could eventually be evolved into small molecules or other biologics with better pharmacological properties.
The Limits of AI in Structural Biology
Despite the breakthrough, one technical gap remains. The team has not yet captured the precise experimental structure of how BFT and claudin-4 fit together. The researchers attempted to use artificial intelligence modeling tools, including AlphaFold, but these tools were unable to fully resolve the interaction.
To verify the physical bond, the Johns Hopkins team worked with structural biologists F. Xavier Gomis-Rüth and Ulrich Eckhard at the Molecular Biology Institute of Barcelona. Using biophysical techniques, they confirmed that BFT and claudin-4 form a tight, one-to-one complex.
Frequently Asked Questions
What is Bacteroides fragilis?
It is a common gut bacterium found in up to 20% of healthy people, though certain strains produce toxins that can cause inflammation and cancer.
How does the BFT toxin cause cancer?
According to research from the Sears lab, BFT cuts E-cadherin, which breaks down the colon’s protective barrier and triggers chronic inflammation that promotes tumor growth.
Can the claudin-4 receptor be blocked?
Yes. Researchers have successfully used a soluble claudin-4 “decoy” in mice to stop the toxin from attaching to colon cells.
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