SARS-CoV-2 Nsp1 blocks protein synthesis and innate immune activation
The novel pandemic Coronavirus SARS-CoV-2 is known to effectively evade human immune defenses. In a close collaboration, the team of Prof. Roland Beckman from the LMU Munich and the labs of Dr. Konstantin Sparrer and Prof. Frank Kirchhoff at the Institute of Molecular Virology, Ulm now revealed the molecular details on how the accessory protein Nsp1 of SARS-CoV-2 shuts down the ribosome and consequently major anti-viral defense systems. Using high-resolution cryo-electron microscopy (cryoEM) the team of Prof. Beckmann reconstructed the structure of SARS-CoV-2 Nsp1 binding to the human ribosome. Notably, the binding interface between Nsp1 and the ribosome is conserved among SARS-CoV-2 and other highly pathogenic coronaviruses, i.e SARS-CoV and MERS-CoV. By inserting two alpha helices into the mRNA entry tunnel, Nsp1 effectively prevents mRNAs from entering the ribosom. Thus, the cellular protein production is shut down. As a consequence, the team of Dr. Konstantin Sparrer could show that the induction of major innate immune signaling pathways, that depend on de novo protein production, is almost completely prevented. For example, induction of antiviral interferons and important immune signaling pathways are affected.
Taken together, this study revealed in molecular detail how SARS-CoV-2 utilizes Nsp1 to hijack the cell metabolism and to shut down anti-viral defenses. Targeting the interaction between Nsp1 and the ribosome using Nsp1 mimicking peptides may be a promising future therapeutic approach to achieve effective immune control of SARS-CoV-2.
The study was published in the international journal Science.
Matthias Thoms, Robert Buschauer, Michael Ameismeier, Lennar Koepke, Timo Denk, Maximilian Hirschenberger, Hanna Kratzat, Manuel Hayn, Timur Mackens-Kiani, Jingdong Cheng, Jan Straub, Christina M. Stürzel, Thomas Fröhlich, Otto Berninghausen, Thomas Becker, Frank Kirchhoff, Konstantin M.J. Sparrer, Roland Beckmann: Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2, Science 2020, 17 July https://doi.org/10.1126/science.abc8665