How SARS coronaviruses reprogram host cells to their own advantage

Coronavirus researchers led by Professor Rolf Hilgenfeld of the University of Luebeck and PD Dr Albrecht von Brunn of the Ludwig-Maximilian Universitaet (LMU) in Munich have discovered how SARS viruses enhance the production of viral proteins in infected cells, so that many new copies of the virus can be generated. Notably, coronaviruses other than SARS-CoV and SARS-CoV-2 do not use this mechanism, which may therefore provide a possible explanation for the much higher pathogenicity of SARS viruses. The results appear in the EMBO Journal.

Coronaviruses that cause harmless colds in humans were discovered over 50 years ago. When it first appeared in 2002/2003, the SARS coronavirus was the first coronavirus to cause severe pneumonia in those infected. Comparisons of harmless coronavirus RNA genomes with those of the SARS coronavirus allowed researchers to identify a region that only appeared in the latter, and which was called the “SARS single domain” (SUD). These genomic regions and their protein products may be linked to the extraordinary pathogenicity of the SARS coronavirus and its cousin, the COVID-19 SARS-CoV-2 virus.

Research groups led by Hilgenfeld and von Brunn have shown that the SUD proteins of these two viruses interact with a human protein called Paip-1, which is involved in the early stages of protein synthesis. Along with Paip-1 and other proteins in human cells, SUD apparently binds to ribosomes, the molecular machinery responsible for protein synthesis in cells. This would lead to an increase in the production of all proteins, both those of the host cell and those of the virus. However, in cells infected with SARS-CoV or SARS-CoV-2, the messenger RNA molecules that code for the host proteins are selectively destroyed by a viral protein called Nsp1. Due to this complicated process, the infected cell mainly produces viral proteins, so that many new copies of the virus can be created.

Albrecht von Brunn’s research group discovered the interaction between SUD and Paip-1 proteins several years ago. “Being an experienced coronavirologist, I knew you had to inspect special regions of the SARS genome to try to understand this virus,” he says.

The discovery made by the Munich researchers was of great interest to Hilgenfeld, whose research group had already elucidated the three-dimensional structure of the SUD protein a few years earlier. The two research groups have joined forces. Dr Jian Lei of the Hilgenfeld group, in the meantime group leader at Sichuan University in Chengdu (China), succeeded in crystallizing the complex formed by SUD and Paip-1 and in determining its three-dimensional structure by ray crystallography. X. And co-first author Dr. Yue “Lizzy” Ma-Lauer of the von Brunn group characterized the complex of the two proteins and its function using a variety of biological and cellular biophysical methods.

“Such interaction studies between coronavirus proteins and proteins in the infected human cell will help us understand how viruses alter key cell functions to their own advantage,” says Hilgenfeld. The project was supported by the German Federal Ministry of Education and Research (BMBF) and the German Infection Research Center (DZIF).

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