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Toxins force building ‘roads to nowhere’: discovery is first report of effect on abundant actin protein

Toxins released by a type of bacteria that causes diarrhea hijack cell processes, forcing important proteins to assemble together in “roads to nowhere,” diverting the proteins away from other tasks necessary for proper cell function are crucial, a new study has found.

The proteins involved are known as actins, which are very abundant and have multiple functions, including helping each cell unite its contents, maintain its shape, divide, and migrate. Actins assemble into thread-like filaments to perform specific tasks in cells.

Researchers found that two toxins are produced by the vibrio Bacterial species cause actins to connect to these filaments in the wrong places within cells—which you might think of as cellular highways carrying cargo—and be directed in the wrong direction.

“Growing in the wrong direction is an entirely new function that was previously unknown and not thought possible for actin filaments within the cell,” said senior author Dmitri Kudryashov, associate professor of chemistry and biochemistry from the Ohio State University. “A large portion of the actin in the cell is consumed in the formation of ‘highways’ where it is not needed, so the cell’s resources are wasted and cannot be used to meet the cell’s basic needs.”

The research is published in the journal today (November 18, 2022). scientific advances.

These troublesome toxins are called VopF and VopL and are produced by two strains vibrio Bacteria living in sea water: V. cholerae and V. parahaemolyticusboth of which can contaminate oysters and other shellfish that make people sick if eaten raw.

In this study, the research team focused on describing the unexpected cellular activities rather than further implications, such as B. the connection between the kidnapping and the bacterial infection.

“We’re looking at the interference at the molecular level — we didn’t focus here on how this cellular function might affect humans,” said first and co-corresponding author Elena Kudryashova, a chemistry and biochemistry research scientist at Ohio State.

“From a practical standpoint, this tells us more about these pathogens, and if you know your enemy, you can fight your enemy,” she said. “But finding something we didn’t know was possible — that actin behaves this way in the cell — raises new questions about whether this function is actually required or might come about in some other way.”

Means have heretofore been known for assembling each filament in a manner starting from what is known as its pointed end and directed towards what is the barbed end of the structure. Being limited in number, the actins are broken down from the pointed end and recycled as needed to maintain directional activity toward the barbed end—and then these actin filaments perform functions such as cell migration, contraction, or division as the cell commands .

However, when the toxins VopF and VopL enter a cell, they attract actin molecules to start a new filament, causing the filaments to assemble at that point, causing them to elongate toward the sharp end—a reversal of their usual direction of stretching.

“The toxins start building these actin filament highways in the wrong place and building something that’s useless to the cell, and the cell doesn’t know how to deal with it,” Kudryashov said.

This actin interference was observed by imaging live cells containing single toxin molecules. Although they don’t yet know all the consequences of this hijacking activity, the researchers said the findings could include the leakage of nutrients through damaged gut walls – which would provide sustenance for the infectious bacteria waiting outside.

“Killing cells is not always necessary – disrupting the barrier function of cells can also be beneficial for pathogens,” said Kudryashova.

And that’s why the scientists want to know more – whether other molecules can force actins to build “roads to nowhere” and whether this strange filament formation could even be a useful mechanism in other circumstances.

“It’s entirely possible that our own cells do this on occasion, but we don’t know because actin has so many functions and not all of them are well understood yet,” Kudryashov said.

The Ohio State team worked with co-authors Ankita, Heidi Ulrichs, and Shashank Shekhar of Emory University.

This work was supported by grants from the National Institutes of Health.

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