Researchers Identify Antiviral Mechanisms of Protein Complex That Could Help Establish Therapeutic Targets Against Hepatitis B Virus

Understanding the function of a protein complex could help to create an effective therapeutic treatment for hepatitis B virus (HBV), according to a study published in Nature Structural and Molecular Biology. Researchers at UNIGE collaborated with Gilead Sciences to identify 3 mechanistic steps of the 6-protein complex, SMC5/6. There are currently no effective treatments for HBV.

The UNIGE team originally discovered the large SMC5/6 protein complex in 2016. Michel Strubin, an associate professor at the UNIGE Faculty of Medicine, led the research efforts.

SMC5/6 proteins are part of SMC, which is a larger family of protein complexes.

SMC5/6 functions by detecting the DNA in HBV and blocking it. However, HBV produces an X protein that can degrade SMC5/6 and the result is that SMC5/6 can no longer defend the body against HBV.

In this study, UNIGE researchers set out to understand whether other proteins in the SMC complex could bind to DNA of HBV, using in vitro cell cultures to find an answer. They found 3 steps that the SMC5/6 complex takes to defend against hepatitis B.

‘‘In the first step, a protein of the SMC5/6 complex detects the virus’ DNA and traps it,” said first author Fabien Abdul, a senior research and teaching assistant at the UNIGE Faculty of Medicine, in a press release.

The next step involves a protein called SLF2, according to Abdul. SLF2 “takes the trapped DNA of the virus into a sub-compartment of the nucleus of the attacked cell, called the PML body.” Thirdly, a protein called Nse2 inhibits the chromosome of the virus.

HBV is the most common form of hepatitis, being transmitted through biological fluids. Because HBV attacks liver cells and can be 100 times more contagious than HIV, it can be considered a serious infectious disease.

Chronic HBV can lead to complications such as liver cancer and cirrhosis. The disease and its complications result in the death of nearly 1 million people each year worldwide. Vaccination is currently the only effective option for HBV, but it is only preventative against the virus.

The research team used molecular biology techniques to determine the antiviral mechanisms of the SMC5/6 complex. Using genetic scissors such as CRISPR-Cas9, the team deleted, or modified, the genetic code of each protein in SMC5/6, Strubin explained in the press release. “Thanks to this technique, we were able to make one or other of the proteins disappear and thus understand their respective functions within the complex,” he said.

Going forth, researchers will begin looking at the X protein to understand how hepatitis B overcomes the antiviral function of SMC5/6. “The next stage of research will consist of better deciphering the mechanism of inhibition of the virus in the sub-compartment of the cell nucleus,” said Aurélie Diman, a postdoctoral researcher in Strubin’s laboratory, in the press release.

Reference

Universite´ de Genevè. The cell sentinel that neutralises hepatitis B. EurekAlert. October 4, 2022. Accessed on October 4, 2022. https://www.eurekalert.org/news-releases/966665