Study from the US state of Ohio reveals bacterial defense mechanism against phages

Study from the US state of Ohio reveals bacterial defense mechanism against phages

One of the many secrets of bacteria's success is their ability to defend themselves against viruses called phages, which infect bacteria and use their cellular machinery to make copies of themselves.

Technological advances have recently made it possible to identify the proteins involved in these systems, but scientists are still delving deeper into how these proteins function.

In a new study, a team from Ohio State University has reported the molecular makeup of one of the most common anti-phage systems - from the family of proteins called Gabija - which is estimated to be used by at least 8.5% and up to 18% of all bacterial species on Earth.

Researchers discovered that a protein appears to have the ability to fight off a phage. However, when it binds to a partner protein, the resulting complex is extremely adept at cutting the genome of an invading phage, rendering it unable to replicate.

We hypothesize that the two proteins must form a complex to play a role in phage prevention. But we also believe that a protein alone has a certain anti-phage function. The full role of the second protein requires further investigation.”

Zhangfei Shen, co-lead author of the study and postdoctoral fellow in biological chemistry and pharmacology at Ohio State's College of Medicine

The results contribute to scientific understanding of the evolutionary strategies of microorganisms and could one day be translated into biomedical applications, researchers say.

Shen and co-lead author Xiaoyuan Yang, a graduate student, work in the lab of lead author Tianmin Fu, assistant professor of biological chemistry and pharmacology at Ohio State.

The study was published on April 16Structural and molecular biology of nature.

The two proteins that make up this defense system are called Gabija A and Gabija B, or GajA and GajB for short.

Researchers used cryo-electron microscopy to determine the biochemical structures of GajA and GajB individually, as well as a so-called supramolecular complex, GajAB, which forms when the two combine into a cluster made up of four molecules of each protein.

In experiments withBacillus cereusUsing bacteria as an example, the researchers observed the activity of the complex in the presence of phages to gain insights into how the defense system works.

Although GajA alone showed signs of activity that could deactivate a phage's DNA, the complex it formed with GajB was much more effective at ensuring that phages could not take over the bacterial cell.

“That’s the mystery part,” Yang said. "GajA alone is enough to cleave the phage core, but it also forms the complex with GajB when we incubate them together. Our hypothesis is that GajA recognizes the phage's genome sequence, but GajB enhances this recognition and helps cut the phage DNA." “

The large size and elongated configuration of the complex made it difficult to get a complete picture of the functional contributions of GajB when bound to GajA, Shen said, so the team had to make some assumptions about the protein roles that have yet to be confirmed.

"All we know is that GajB helps increase GajA activity, but we don't yet know how it works because we only see about 50% of it in the complex," Shen said.

One of their hypotheses is that GajB could influence the concentration of an energy source, the nucleotide ATP (adenosine triphosphate), in the cellular environment - specifically, by lowering ATP after detecting the phage's presence. This would have the dual effect of expanding GajA's phage DNA-deactivating activity and stealing energy that a phage would need to begin replicating, Yang said.

There is still more to learn about bacterial anti-phage defense systems, but this team has already shown that blocking virus replication is not the only weapon in the bacterial arsenal. In a previous study, Fu, Shen, Yang and colleagues described a different defense strategy: bacteria program their own death rather than allowing phages to take over a community.

This work was supported by the National Institute of General Medical Sciences.

Additional co-authors include Jiale Xie, Jacelyn Greenwald, Ila Marathe, Qingpeng Lin and Vicki Wysocki from Ohio State and Wenjun Xie from the University of Florida.

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