This is the mechanism that helps viruses like monkeypox to block the cellular defense system.

A defense mechanism that human cells have against viruses such as monkeypox, herpes simplex, and human papillomaviruses — all double-stranded DNA viruses — relies on proteins that patrol the cell as sensors for the DNA of the virus. It is a type of cellular defense discovered barely a decade ago and still little studied. When the sensor proteins detect viral DNA, they bind to it, and then the alarm goes off: the cell activates its defenses. But the virus, like in an arms race, also has proteins capable of blocking this cellular alarm system.

One of these proteins that alerts cells to the presence of DNA viruses is the protein complex called ku. Scientists from the CNIO and the University of Sussex have now managed to characterize its three-dimensional structure at the atomic level, coupled to that of the viral proteins capable of blocking this complex. The finding, which is published in the journal Nature Communications, will improve the response to these infections.

Researchers have worked with the Vaccinia virus (used in the development of the smallpox vaccine and belonging to the poxvirus family). Two proteins of this virus, called C4 and C16, bind to Ku and block its action, thus inactivating the cellular immune response. Knowing the shape of these proteins, their three-dimensional structure, helps to understand how they do it.

Proteins as plugs to inactivate the Ku ring

Ku is ring-shaped, with a central hole that it uses to thread itself into DNA. Researchers have discovered that the two virus proteins act as plugs that plug that gap, blocking Ku’s ability to recognize viral DNA (see graphic animation).

Researchers from the CNIO group on Macromolecular Complexes in Response to DNA Damage, led by Óscar Llorca, have managed to obtain the structure of the C16-Ku complex through cryoelectron microscopy, a technique that allows visualizing the interactions between the viral protein and the human protein.

In this way, the authors of the work have been able to identify which part of the viral protein causes Ku blockade. “The Ku heterodimer forms a kind of ring that is linked to DNA. The virus protein acts as a kind of stopper for this ring, thus blocking the binding of Ku to viral DNA”, explains Óscar Llorca.

The work has been carried out in collaboration with the group from the University of Sussex (United Kingdom) led by the researcher Laurence H. Pearl, who has confirmed that the mechanism of action of the C4 protein is very similar to that of C16.

Block Ku from helping tumor cells

The ku complex is also present in the nucleus of cells, but its role there is not to warn of the presence of viruses but to repair our own genetic material when it is damaged.

Llorca’s group studies the role in cancer of protein complexes such as ku, involved in the repair of double-stranded DNA. When these repair mechanisms act on tumor cells, they are favoring their survival, and therefore cancer. Now that it is known, thanks to the new work, how viruses block the action of ku, its role in DNA break repair could be learned to be altered of tumor cells.

«The idea for this research arose because if in a treatment to generate damage to the DNA of tumor cells we could block the functioning of Ku during the DNA repair process, in a similar way to how viruses do, the treatment would still be more effective,” says Ángel Rivera-Calzada, co-lead author of the study.

In this way, one of the next steps will be to evaluate whether emulating the mechanism of viral proteins to block Ku would serve to develop a strategy that will amplify the effect of cancer treatments.

Knowing the shape of these proteins, their three-dimensional structure, helps to understand how they do it.

“Of all the viral protein, it is a portion of a few amino acids that acts by blocking the action of Ku,” says Rivera-Calzada. The first step would be to confirm that those small fragments produced in the laboratory sare capable of blocking DNA recognition damaged. To this end, the authors of the paper trust in collaborating with CNIO experts in this type of strategy.

Deepen its role against viral infections

In addition, the information obtained could help the development of strategies against infections caused by these viruses. Comparing the protein sequences of the C4 and C16 homologues in other viruses of the family, researchers have been able to observe that the regions involved in Ku inactivation are highly conserved. Among these viruses are, for example, the smallpox virus or the monkeypox virus, which has recently been in the news due to the appearance of multiple cases in different European countries. To this end, the researchers propose future collaborations with specialist groups in virology.

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