Bacterial Defense System and Its Demise

If you’ve seen the original Star Wars film, you might be wondering if the iconic Tie fighter was inspired by the Gabija protein complex, a bacterial defense system.

They appear to have the same characteristic shape from a specific angle: a lethal center protected by two wings. They also have a same goal: to protect the realm.

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However, Gabija’s structure was only recently disclosed. It was solved for the first time in the lab of Philip Kranzusch, professor of microbiology at Harvard Medical School and Dana-Farber Cancer Institute, by virology doctorate candidate Sadie Antine.

Their findings were published in the journal Nature.

Understanding Gabija and other components of bacterial defense systems, as well as the mechanisms used by viruses known as phages to overcome these defenses and infect bacteria, promises to shed light on broader aspects of immunity, such as human immunity and immune responses to cancer.

In the evolutionary arms race between bacteria and phages, the team has already identified an unanticipated technique that phages may utilize to destroy Gabija.

“This is the importance of basic science,” said Kranzusch, the paper’s senior author. “We’re learning how cells defend against infection.”

A picture of the protein complex
Gabija is one of hundreds of bacterial defensive systems. It is found in around 15% of all bacteria whose genes have been sequenced.

“It’s one of the most prevalent bacterial defense systems,” says Antine, the study’s first author. “Yet very little was known about how it works or how viruses that infect bacteria can evade the system.”

Antine employed X-ray crystallography to learn what Gabija looks like as a fully formed molecular machine, also known as a protein complex. Coaxing the bacteria to produce the protein complex, crystallizing the complex to make it immobile, and scattering X-rays off it to obtain an atomic-level 3D picture of the structure are all steps in the process.

“It was a surprising result that changes the way we think about how phages interact with these defense systems.”- Sadie Antine

Gabija, she discovered, is a massive complex. It is roughly one-quarter the size of the ribosome, which is a massive molecular machine that uses information from RNA to produce proteins.

Antine also discovered that Gabija is created utilizing only two genes, GajA and GajB. GajA assembles proteins into groups of four to form the structure’s core. GajB generates proteins that link to produce the structure’s outer winglike parts.

“It’s an arrangement that you never would have guessed until you did the experiments,” Kranzusch told me.

It’s unclear how this massive structure recognizes and destroys the phage. Antine and Kranzusch believe the complex identifies and destroys a specific structure generated by phage DNA.

“Gabija has exquisitely evolved to hunt and destroy a very particular target,” Kranzusch told me.

Antine and Kranzusch worked with a team from the Weizmann Institute in Rehovot, Israel, to discover Gabija as a defense mechanism of interest and the phage that can avoid it.

With this knowledge, Antine introduced a gene known to make the phage elusive into bacteria that produce Gabija to learn more about phage evasion techniques.

Antine was interested in watching Gabija interact with the phage protein. She employed cryo-electron microscopy (cryo-EM) to do this, which entails super-cooling the complex and employing an electron beam to make a 3D image of the system.

“With crystallography we see a snapshot of the protein complex in a rigid state,” Antine went on to say. “But with cryo-EM, it is possible to analyze flexible complexes, and you can see how the interaction has played out.”

A common evasive maneuver would be for the phage to change the bit of DNA that Gabija detects such that Gabija does not identify it.

It went unnoticed. However, the phage does not do so, implying that the DNA Gabija detects is required for the phage to survive.

Another frequent strategy is for the phage to develop a piece of DNA that encodes a tiny protein that interferes with Gabija’s critical machinery. But Antine didn’t notice either.

Rather, she discovered that the phage developed DNA that encodes a big protein that surrounds and inactivates Gabija.

“The protein forms this huge web around the entire outside of the complex,” Kranzusch added. “This method of evasion generates a massive complex.” It was an unexpected revelation that alters our understanding of how phages interact with these defense mechanisms.”

Molecular superiority
Phages are frequently assumed to be small and simple, however Kranzusch discovered that this is not always the case. The phages he and Antine are examining are massive, with hundreds of genes encoded in their DNA.

Because they require a host cell to multiply, phages are considered entities rather than living organisms. Nonetheless, they actively evolve and change in response to pressure from defense systems such as Gabija.

“They are complex, evolving and adapting with their host.” “They shape evolution,” Kranzusch remarked.

Antine will investigate the specific techniques Gabija employs to fight phages in the coming steps. These mechanisms are the outcome of each side devising new methods of defeating the other. The similar form of one-upmanship occurs in cancer, as tumor cells become more adept in evading the immune system and cancer treatments.

“There are parallels between immunity in human cells and in bacteria,” Antine said. “We’re interested in the diversity, the many ways that immune systems combat something that is actively evolving against it.”

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