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The enzyme Cas13 protects the bacteria from DNA viruses by targeting the RNA of the host cell. Until now, the strategy has never been observed in bacteria.
What does not kill a bacterium makes it stronger.
An enzyme that bacteria use to fight viruses works by targeting not only the virus but also the bacteria itself. It sends the bacteria in the dormant state and makes it an inhospitable place in which viruses reproduce. This protects bacteria from mutated viruses that slide beyond other immune defenses, researchers report on May 29, 2019, in the newspaper, Nature.
Disarming or killing host cells is a common strategy of the immune system, but this new work is the first to demonstrate it for bacterial CRISPR defense, says molecular biologist Luciano Marraffini, an investigator at the Howard Hughes Medical Institute at Rockefeller University.
The Cas13 enzyme was discovered in 2015 and is part of a family of proteins best known for their role in gene editing. In the popular CRISPR tool, for example, scientists have leveraged the Cas9 enzyme to insert or modify specific genes. In nature, Cas proteins are a key component of bacterial immune systems. They disable viruses that infect bacteria by cutting DNA or RNA from invaders.
Scientists already knew that Cas13 was a bit weird in his family. If Cas9 is a scalpel, Cas13 is rather a machete. It cuts in specific and targeted places, but also cuts the target. And unlike most Cas proteins, it cuts RNA, not DNA.
"Cas13 has already become a very powerful diagnostic tool," says co-author of the study, Alexander Meeske, also at Rockefeller. Researchers can use it to quickly identify viruses present in the blood of patients, even those present at very low concentrations. "What we do not know," he explains, "is how Cas13's behavior affects bacterial immunity."
<img alt = "" clbad = "caption" src = "http://www.hhmi.org/sites/default/files/crispr_interactive_draft_gif_v2_2.gif" style = "width: 715px; height: 460px;" title = "In the genome editing technology known as CRISPR-Cas9, RNA (blue) forms a complex with the Cas9 protein (bumpy structure). Cas9 unwinds the target DNA (in red) and acts as a molecular scalpel slicing both strands Cas13, a related protein, cuts RNA instead of DNA. HHMI BioInteractive, CRISPR-Case 9 Mechanism and Applications"/>
Now, he and his colleagues have found Cas13's seemingly random breakages a valuable bacterial defense tool. While most Cas enzymes protect bacteria by preventing viruses from reproducing, Cas13 disables the bacterial host itself.
This is important because viruses can easily escape CRISPR systems – a simple genetic mutation in the region that Cas's target enzymes can make the virus invisible to the immune system. Researchers have shown that Cas13 can catch these potential "escaped" viruses.
First, Meeske and his colleagues badyzed how Cas13 affected RNA. They discovered that the enzyme had largely cleaved RNA, breaking down the RNA produced by the virus and the host cell. Even when Cas13 cut completely disposable RNA regions for the virus, the viruses still could not reproduce. This suggested that the host cell was in a way stopping viral reproduction.
When Meeske then developed mutated viruses that Cas13 could not recognize, the viruses multiplied Listeria bacteria. But the addition of normal unmutated viruses and mutated viruses effectively protected the cells from infection – they forced Cas13 to light up and chop all the cell's RNA, he says. "It was so counterintuitive and surprising!"
Without RNA, bacterial cells could not continue to grow and function. And in cells that do not work, the mutant virus can not multiply.
It's unclear whether cells can bounce off this dormancy or if they eventually die, says Meeske. But by preventing viruses from replicating, these cells protect the largest bacterial population from the threat.
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Alexander J. Meeske, Sandra Nakandakari-Higa and Luciano A. Marraffini. "Cas13-induced cell dormancy prevents the rise of CRISPR-resistant bacteriophage." Nature. Posted online 29th May 2019. doi: 10.1038 / s41586-019-1257-5
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