Cellular junctions controlling toxin entry

Cellular Lock-and-Key: How Junctions Control Toxin Entry

Reese Marlowe in Science & Nature September 2025 • 3 min read.

"Discover how a novel cellular mechanism regulates toxin entry, offering new insights into infection defense and potential therapeutic targets."

Our bodies are constantly bombarded by potential threats, from bacteria to viruses. Epithelial cells, which line our surfaces and act as the first line of defense, are particularly vulnerable. These cells are held together by specialized structures called cell-cell junctions, which maintain tissue integrity. But what if these junctions could also be manipulated by pathogens to gain entry?

Pore-forming toxins, secreted by bacteria, insert themselves into cell membranes, creating pathways for cellular damage. Staphylococcus aureus, a common bacterium, produces alpha-toxin, which targets a receptor protein called ADAM10 on our cells. This interaction leads to pore formation and, ultimately, cell death. Until recently, scientists didn't fully understand how cells regulated this process.

A recent study sheds light on the intricate dance between bacterial toxins and cell junctions. Researchers have uncovered a "dock-and-lock" mechanism that controls how ADAM10 is clustered at cell-cell junctions, influencing the cell's vulnerability to alpha-toxin. This mechanism may hold the key to developing new strategies for preventing bacterial infections.

The Dock-and-Lock: A Molecular Mechanism for Toxin Control

Cellular junctions controlling toxin entry

The research team identified key proteins involved in this process: PLEKHA7, PDZD11, Tspan33, and afadin. These proteins work together to cluster ADAM10 at cell-cell junctions, specifically adherens junctions. The process unfolds as follows:

Tspan33, a transmembrane protein, acts as the "dock" by binding to ADAM10. It then uses its cytoplasmic tail to connect with PLEKHA7.

PLEKHA7, along with PDZD11, creates a complex that acts as the "lock," securing Tspan33 and ADAM10 at the junction.
Afadin then binds directly to ADAM10, further stabilizing the cluster.
This clustering promotes the efficient formation of stable toxin pores, increasing the cell's susceptibility to alpha-toxin.

Conversely, when the PLEKHA7-PDZD11 complex is disrupted, ADAM10 cannot be effectively clustered at junctions. This leads to increased toxin pore removal through endocytosis, a process where the cell engulfs and internalizes the pores. As a result, cells become more resistant to the toxin and have a greater chance of survival.

Future Implications: Targeting Junctions for Infection Control

This discovery offers a new perspective on how cells regulate their interactions with pathogens. By understanding the precise mechanisms that control ADAM10 clustering at cell-cell junctions, researchers can explore novel therapeutic strategies to combat bacterial infections. These strategies might involve:

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Everything You Need To Know

What is the role of cell-cell junctions in toxin entry?

Cell-cell junctions, specifically adherens junctions, are crucial structures that hold cells together, maintaining tissue integrity. Recent research has revealed that these junctions also play a significant role in controlling the entry of harmful toxins into cells. This is significant because it shows that pathogens can manipulate cell-cell junctions to gain entry. Understanding the function of cell junctions gives insights to create future therapies.

Could you explain what is meant by the "dock-and-lock" mechanism?

The "dock-and-lock" mechanism refers to the molecular process by which ADAM10 is clustered at cell-cell junctions, influencing a cell's vulnerability to alpha-toxin. Tspan33 acts as the "dock" by binding to ADAM10, then connects with PLEKHA7. The PLEKHA7-PDZD11 complex acts as the "lock," securing Tspan33 and ADAM10 at the junction, with afadin further stabilizing the cluster. This mechanism regulates toxin entry, providing new therapeutic strategies to fight bacterial infections.

What is the role of ADAM10 in bacterial toxin entry?

ADAM10 is a receptor protein on our cells targeted by alpha-toxin, which is produced by Staphylococcus aureus. This interaction leads to pore formation in the cell membrane and, ultimately, cell death. The clustering of ADAM10 at cell-cell junctions, facilitated by the "dock-and-lock" mechanism, promotes the formation of stable toxin pores, increasing the cell's susceptibility to alpha-toxin. Therefore, controlling ADAM10 clustering is crucial in determining a cell's resistance or vulnerability to bacterial toxins.

How do PLEKHA7 and PDZD11 influence toxin resistance?

PLEKHA7 and PDZD11 work together to create a complex that acts as the "lock" in the "dock-and-lock" mechanism, securing Tspan33 and ADAM10 at the adherens junction. When this complex is disrupted, ADAM10 cannot be effectively clustered at junctions, leading to increased toxin pore removal through endocytosis. This disruption makes cells more resistant to toxins and increases their chance of survival, highlighting the importance of this complex in regulating toxin entry.

What are the future implications of this research for infection control?

Targeting junctions for infection control involves developing therapeutic strategies that manipulate the "dock-and-lock" mechanism to prevent bacterial infections. This could involve disrupting the PLEKHA7-PDZD11 complex to inhibit ADAM10 clustering or enhancing endocytosis to remove toxin pores more efficiently. These strategies aim to increase cells' resistance to toxins and reduce the severity of bacterial infections. Further research into the precise mechanisms controlling ADAM10 clustering at cell-cell junctions is essential for developing these novel therapies.