Viral shutdown of the protein synthesis method found

Researchers from Munich and Ulm have determined how the SARS-CoV-2 pandemic coronavirus inhibits protein synthesis in infected cells and has shown that it effectively disarms the body’s innate immune system.

Although its name is relatively nonspecific and indeed opaque, the nonstructural protein 1 (Nsp1) encoded by the SARS-Cov-2 coronavirus, which is responsible for the current pandemic, has now been shown to have a devastating effect on host cells. Nsp1 is, in fact, one of the core weapons used by the virus to ensure its own replication and spread in human hosts. Nsp1 was identified as a virulence factor after the SARS-related coronavirus outbreak nearly 20 years ago, when it was shown to inhibit protein synthesis in infected cells. Now, researchers at the Ludwig-Maximilians-Universitaet (LMU) in Munich and the University Hospital of Ulm have discovered what makes Nsp1 so powerful. In an article that appears in the magazine. Science, describe the mode of action of the protein in detail.

In all biological cells, the task of synthesizing proteins is performed by complex molecular machines known as ribosomes. Ribosomes interact with messenger RNAs (mRNAs), which serve as models for protein synthesis, and translate the nucleotide sequence of each mRNA into the amino acid sequence of the corresponding protein. The amino acid sequence in turn determines the shape and biological function of each individual protein. Ribosomes consist of two distinct subunits, and Nsp1 binds to the smallest, the 40S subunit. The mRNA initially binds to the small subunit before the latter interacts with the 60S subunit to form the cavity through which the mRNA is threaded.

The new study shows that one end of the Nsp1 protein interacts with the 40S subunit in such a way that it prevents mRNA binding. With the help of high-resolution cryoelectron microscopy, Professor Roland Beckmann and his colleagues at the LMU Gene Center have demonstrated in three-dimensional detail how Nsp1 firmly binds to a specific pocket in the small ribosomal subunit and inhibits the formation of functional ribosomes. . Other experiments revealed that Nsp1 can also interact with specific configuration states of the fully assembled ribosome.

Furthermore, the team led by Konstantin Sparrer at the University Hospital of Ulm was able to demonstrate that shutting down protein synthesis leads to an almost complete collapse of one of the body’s main lines of defense against the virus. Nsp1 inactivates the innate immune response by inhibiting a vital signaling cascade. The authors of the study hope that the knowledge acquired will allow finding ways to neutralize the new coronavirus and mitigate the severity of the respiratory disease it causes. A potential approach, they say, would be to develop a molecule that masks the binding site of the viral protein. This should be feasible, since the Nsp1 binding pocket does not appear to play an essential role in ribosomal function.