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The hepatitis B-neutralising cell sentinel

ANI Oct 05, 2022

One of the most severe and prevalent viral diseases is caused by the hepatitis B virus (HBV).

It targets the liver cells after being transmitted by bodily fluids. Serious problems from the chronic form of the illness can develop such as cirrhosis and liver cancer.

The chronic version of the illness has no proven cure; immunisation is the only effective means of prevention. A team from the University of Geneva (UNIGE) has unravelled the precise operation of this defensive mechanism after finding a crucial protein complex that is active when our body is infected by the virus, paving the path for novel treatment targets.

The Nature Structural and Molecular Biology journal publishes these findings. The most prevalent type of hepatitis is hepatitis B.

The hepatitis B virus is the cause of the viral illness. Mostly, it is spread through blood or sexual contact. It can spread up to 100 times faster than HIV. This virus infects the liver cells, resulting in a brief inflammation of the liver that may progress to a chronic infection.

Serious diseases like cirrhosis or liver cancer can result from this. According to estimates, this illness claims over one million lives each year throughout the world. Chronic hepatitis B does not have a permanent cure. It can only be avoided by receiving a vaccination before the illness manifests.

A UNIGE team led by Michel Strubin, an associate professor in the department of microbiology and molecular medicine and in the Geneva Centre for Inflammation Research at the UNIGE Faculty of Medicine, discovered a mechanism for this disease in 2016 that is essential for understanding: when our immune system defends itself against it, a complex, or interdependent set, of six proteins called SMC5/6, present in our cells, detects the viral DNA and blocks it.

The virus subsequently responds by producing the X protein, a unique protein. SMC5/6 is degraded by this protein as it enters the cell, rendering it incapable of performing its sentinel function.

A three-step mechanism

The antiviral role of SMC5/6 was unknown prior to this finding. It was only found to be a crucial complex for maintaining the structural integrity of our chromosomes.

Michel Strubin's group achieved fresh success. In a recent study, the UNIGE researchers determined the three processes and the specific proteins needed for SMC5/6 to perform its antiviral function in association with the American pharmaceutical company Gilead Sciences.

''In the first step, a protein of the SMC5/6 complex detects the virus' DNA and traps it'', explains Fabien Abdul, a senior research and teaching assistant in the Department of Microbiology and Molecular Medicine at the UNIGE Faculty of Medicine and first author of the study.

''Then, a second protein of the complex - SLF2 - takes the trapped DNA of the virus into a sub-compartment of the nucleus of the attacked cell, called the PML body. A third protein - Nse2 - then comes into play and inhibits the virus' chromosome.''

As SMC is a large family of protein complexes, the researchers also wanted to know whether other 'members' of this family were able to bind to hepatitis B viral DNA. ''We discovered that this competence was unique to SMC5/6'', says Fabien Abdul.

Towards new therapeutic targets

The research team used in vitro cell cultures to get these results. "We employed molecular biology methods, more especially the CRISPR-Cas9 genetic shears. We were able to use this technology to cut the DNA strands inside of the cells, deleting or changing the genes responsible for each protein that makes up the SMC5/6 complex."

Michel Strubin, the study's last author, adds that by using this technique, "We were able to make one or both of the proteins disappear and so understand their separate functions within the complex." These observations could be used to establish the three phases of the antiviral process.

This finding helps us comprehend the complex's mechanism of action during its antiviral activity. Thus, it might open the door to discovering novel therapeutic targets to fight the hepatitis B virus.

According to Aurelie Diman, a postdoctoral researcher in Michel Strubin's group, "The next stage of research will consist of better elucidating the mechanism of suppression of the virus in the sub-compartment of the cell nucleus."

To fully comprehend how hepatitis B fights the antiviral activity of the cellular SMC5/6, a study on the X protein, whose function was discovered by the UNIGE researchers in 2016, will also need to be done.

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