Study identifies mechanism behind SARS-CoV-2 viral protein production

A new study from German researchers examines how SARS viruses, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), hijack cells and reprogram them to enhance viral replication.

SARS-CoV and SARS-CoV-2 are from the same family of coronaviruses and share similar structural aspects in their RNA genome. Prior research has shown these coronaviruses have a particular region called the SARS-unique domain (SUD), which may be connected to enhanced viral protein production after reprogramming host cells.

The current study extends these findings by looking at the interaction between SUD and the host translation stimulator, Paip-1.

Our study provides new insight on the latter aspect for SARS-CoV by demonstrating that the SUD-N (Mac2) domain interacts with the host cell translation apparatus via Paip1 and increases viral translation. This interaction may offer a new antiviral target.”

Further evidence of SUD-N interaction with Paip1

The researchers characterized the interaction between Paip-1 and the SUD region of the SARS-CoV-2 by creating a 3D structure through X-ray crystallography.

Not only does the SUD-N domain in coronaviruses affect protein translation via Paip1, but the researchers also found the SARS-CoV SUD was almost 75% identical at the amino-acid sequence level. Between the two viruses, the N-terminal shared about 16 residues — needed for Paip1 binding.

Specifically, the researchers confirmed evidence of SUD-N being the region involved in binding with Paip1. The presence of SUD-M, SUD-C, and the X domain is present in the virus, but they did not interact with Paip1.

The SUD proteins of SARS-CoV appeared to start protein translation by interacting with Paip-1. This was shown with a 4.4-fold higher binding affinity of PABP to Paip1. SUD co-elutes the 40S ribosomal subunit marker in 40S and 80S ribosomes, making it a more favorable conformation for binding initiation factors to start protein synthesis.

The SUD binding to Paip-1 stimulates infected cells to produce viral — but not host —proteins. Researchers confirmed the importance of SUD-N binding in making copies of the virus when models deleting the SUD region showed a 10-fold reduction in viral replication.

This is done by the virus’s ability to destroy mRNA coding for host proteins through a viral protein called Nsp1. Nsp1 was found to degrade host mRNA and block host translation when bound to the 40S ribosomes. However, viral RNA can evade Nsp1 degradation resulting in only viral proteins being produced.

The researchers propose the following model:

SUD binds to 40S/80S ribosome and enhances the interaction between Paip1 and PABP to stimulate the general translation level. Then, viral protein Nps1 not only specifically degrades the host mRNAs but also blocks host mRNA binding to the 40S ribosome, leading to the inhibition of host protein synthesis.”

Future implications

Many coronaviruses — such as MERS and SARS — have caused major outbreaks, share the same ACE2 receptor on host cells, and can be found in bats. The SARS-CoV-2 virus was transmitted from bats to humans, and since bats carry many viruses, the researchers suggest the chances of another SARS-like coronavirus outbreak is likely.

Understanding how to target and inhibit viral replication and spread is necessary for containing future zoonotic diseases.

Journal reference:
Jocelyn Solis-Moreira

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.

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