A UBC-led research team has revealed how the virus responsible for causing COVID-19 escapes destruction in infected cells, allowing SARS-CoV-2 to continue and continue to spread in the human body.
The finding explains the cellular coup staged by the new coronavirus and how it disrupts normal cell defense to hijack human host cells.
“We discovered that the virus binds to and deactivates an important sensor protein in the host cell called galectin-8, which protects the cell from infection. By deactivating galectin-8, SARS-CoV-2 disarms a cell’s antiviral defense system and allows the virus to take over the host. , “says Dr. Chris Overall, the study’s senior author, a Canada Research Chair and a lead researcher at the UBC Center for Blood Research, the Life Sciences Institute and the Faculty of Dentistry.
Collectively, a team of local, national, and international collaborators came together to provide samples for this study, which was published in the October 26 issue of Cell reports. The study’s co-lead authors, Dr. Isabel Pablos and Dr. Yoan Machado, are both postdoctoral fellows in his laboratory.
To transform host cells into virus-producing machines, SARS-CoV-2 uses peak proteins that surround the outside of the virus to bind to, invade, and take control of the host.
The researchers made the important discovery that galectin-8 binds to the peak protein. The virus then deactivates galectin-8 by using one of its own key enzymes, called the 3CL protease, to target, bind to, and cut galectin-8 in half, as a molecular scissors.
Galectin-8 protects the host cell from viruses through a defensive response called xenophagy: where an infected cell catches invaders like viruses in small, fluid-filled sacs and then kills them by injecting these sacs with destructive molecules.
“The key enzyme makes a single cut at a specific molecular site in galectin-8, which we accurately identified through a specialized proteomics technique developed in the Overall Lab,” says Dr. Pablos. “This single incision is likely to impair the cell’s ability to destroy the virus.”
Normally, the 3CL protease is a key enzyme that helps viruses replicate, but researchers’ work shows that SARS-CoV-2 has smartly developed a capability that makes its own key enzyme multifunctional, allowing it to maximize its potential.
Using high-resolution microscopic images of COVID-19-infected lungs donated from victims of the disease, the researchers showed that the function of galectin-8 was disrupted in the hard-infected lung cells.
In addition to galectin-8, the researchers also identified about 150 other host cell proteins that are targeted, cut, and inactivated by the virus’ key enzyme. The deactivation of these host proteins is what drives the virus’ ability to take over human cells.
“It’s amazing how the virus can so effectively inhibit a host cell’s normal abilities by targeting and cutting these essential cellular proteins,” says Dr. Machado. “In our study, we identified over 150 molecular sites that are important for basal cell function and are targeted to cut off the virus’ key enzyme.”
The cell is made much more vulnerable to viral takeover when these sites are cut. Four molecular sites that the researchers identified are part of the Hippo signaling pathway, which controls functions such as cell shape, tissue growth and cell death. By cutting these sites, the virus suppresses the ability of the host cell to perform many of its normal functions, creating optimal conditions for SARS-CoV-2 infection.
“By understanding how SARS-CoV-2 inhibits a host cell’s ability to defend itself, and identifying which molecular sites are cut to achieve this, we can finally understand how the virus hijacks the cell,” says Overall.
“This valuable new knowledge enables us to identify new approaches and drugs to target these sites with the aim of preventing the virus from disabling crucial cellular functions – all important insights to guide drug development.”
S-acylation increases COVID-19 infection
Isabel Pablos et al, Mechanical insight into COVID-19 by global analysis of SARS-CoV-2 3CLpro substrate degradation, Cell reports (2021). DOI: 10.1016 / j.celrep.2021.109892
Provided by the University of British Columbia
Citation: Researchers Reveal How SARS-CoV-2 Escapes a Cell’s Antiviral Defense (2021, October 27) Retrieved October 27, 2021 from https://phys.org/news/2021-10-uncover-sars-cov-cell- antiviral-defenses .html
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