Dr. Evan Karousis and Team
Dept. of Chemistry, Biochemistry and Pharmaceutical Sciences
In the early stages of a pandemic, before vaccines are available, therapeutic antivirals play a key role in our pandemic preparedness toolbox. A recent MCID-funded study, published in Cell Reports sheds light on how SARS-CoV-2 uses the viral protein Nsp1 to shut down host protein production. These insights could prove important in the development of next-generation antivirals.
After infecting a cell, SARS-CoV-2 hijacks the host’s translation machinery to produce viral proteins needed for replication and spread. One of the first viral proteins to be made is Nsp1, which acts as a ribosomal gatekeeper, blocking host translation while encouraging SARS-CoV-2 translation. It has been widely accepted that Nsp1 binding to a ribosome is required to stimulate host mRNA degradation, but how this occurs in vivo is unclear.
In this study, the authors found that Nsp1 binding to the 40S ribosomal subunit does not promote ribosomal-associated quality control mechanisms or cause widespread ribosome collisions and may reduce ribosome stalling. These are all tell-tale signs of a host cell that is under duress and demonstrates the stealth techniques the virus uses to avoid detection. To investigate whether active translation is required for mRNA degradation, the team developed a custom-made cell-free translation system. This innovation based on dual centrifugation, generates reproducible translation-competent lysates from human cells while avoiding common artifacts characteristic of traditional in vitro translation systems. This facilitated the uncoupling of translation inhibition from mRNA degradation and allowed independent consideration of each process. Experiments using translation and scanning inhibitors confirmed that while Nsp1 must bind to the ribosome to trigger mRNA degradation, translation inhibition alone is not sufficient. Previously proposed Nsp1 inhibitors failed to inhibit translation in this cell-free system, a further indication that future efforts should focus more specifically on the interaction between Nsp1 and the 40S subunit.
In conclusion, this study offers important key mechanistic insights into how SARS-CoV-2 Nsp1 promotes host mRNA degradation through its binding to the ribosome, independent of ribosome collisions or active translation. In contrast, MERS-CoV Nsp1 inhibits translation without triggering degradation and thereby highlights strategic differences coronaviruses use to subvert host cell machinery. By unravelling the unique biology of Nsp1, this work lays the foundation for more precise antiviral strategies targeting a vulnerability in the coronavirus replication cycle.
Bäumlin E, Andenmatten D, Luginbühl J, Lalou A, Schwaller N, Karousis ED. The impact of Coronavirus Nsp1 on host mRNA degradation is independent of its role in translation inhibition. Cell Reports. 2025 Apr 22;44(4).
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