Apparently, the novel Sars-CoV-2 coronavirus is able to spread through human cells by disrupting the cells’ protein expression. This means that even those proteins that are vital for the body’s immune response system can no longer be produced. At the same time, the virus uses Nonstructural Protein 1 (Nsp1) as its main weapon in order to be able to propagate.
This fact has been known since the SARS coronavirus outbreak of 2002/2003. Back then, scientists established that Nsp1 in the host inhibits protein expression in ribosomes. However, researchers from the German Ludwig Maximilian University of Munich (LMU) and the University Hospital in Ulm have now discovered how Nsp1 specifically attacks and what makes this protein so dangerous.
Blocks entrance to pathways
Ribosomes are involved in protein expression in every biological cell. “To do this, they use sections of so-called messenger RNA (mRNA) as blueprints that then assemble the amino acid chains that fold into intact proteins,” the researchers explain. Ribosomes are made up of two subunits, with the Nsp1 viral protein attacking the smaller, or what is known as the 40S subunit.
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One end blocks the entry tunnel where the messenger RNA with the genetic blueprint normally threads its way through. This causes the molecular mechanism (that creates the amino acid chains after linking to a second subunit) to come to a standstill. The scientists, led by Roland Beckmann, professor at the Gene Center at LMU Munich, were able to use high-resolution cryo-electron microscopy to identify precise 3-dimensional details and subsequently show how Nsp1 attacks.
It then settles in a special sac of the ribosome, locks itself in place, and blocks the entry tunnel. In their experiments, the researchers were also able to show that Nsp1 attacks particular complexes of the complete ribosome as well.
The team led by Dr. Konstantin Sparrer from the University Hospital in Ulm (Universitätsklinikum Ulm) was further able to show that the shutdown of protein expression also leads to an almost total collapse of a crucial line of defense in the fight against viral attacks: “It largely suppresses the innate immune system by blocking a key signaling pathway,” he writes.
Now the scientists hope that their findings will help in discovering new ways to combat COVID-19. It is feasible that a molecule could be used “to mask the viral protein’s point of attack,” they go on to say. The ribosome sac in which the Nsp1 attaches itself is not thought to have an indispensable function for regular protein expression.
Although SARS-CoV-2 has other inhibitors that suppress the innate immune system, disabling the Nsp1 function may render the virus susceptible to eradication by the immune system. “If we can prevent the Nsp1 viral helper protein from binding to ribosomes, we can enable the innate immune system that there is against SARS-CoV-2 to remain functional and effectively control the virus.”
The scientists’ work has been published in the renowned Science magazine.
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