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Source: Coronavirus Latest  Nov 06, 2020  3 years, 3 months, 2 weeks, 1 day, 8 hours, 27 minutes ago

Coronavirus Latest: Yale Study Shows That Nonstructural Protein 1 of SARS-CoV-2 Hijacks Host Protein Synthesis In Ribosomes To Make Viral Proteins

Coronavirus Latest: Yale Study Shows That Nonstructural Protein 1 of SARS-CoV-2 Hijacks Host Protein Synthesis In Ribosomes To Make Viral Proteins
Source: Coronavirus Latest  Nov 06, 2020  3 years, 3 months, 2 weeks, 1 day, 8 hours, 27 minutes ago
Coronavirus Latest: A new study by a multidisciplinary team of Yale researchers has discovered that the nonstructural protein 1 (Nsp1) of the SARS-CoV-2 coronavirus is able to hijack the human host protein synthesis in the ribosomes of the cells in order to produce its own viral proteins.

It has been found that one of the novel coronavirus' most insidious tricks is that it can block the ability of human host cells to produce protective proteins without hindering its own ability to replicate.
The study team discovered that the SARS-CoV-2, the virus that causes COVID-19, accomplishes this trick by blocking production of cellular proteins, including immune molecules, and contributes to severe illness in its host.
According to the study team, the novel coronavirus uses its nonstructural protein 1 (Nsp1) to suppress cellular, but not viral, protein synthesis through yet unknown mechanisms. The researchers showed here that among all viral proteins, Nsp1 has the largest impact on host viability in the cells of human lung origin. Differential expression analysis of mRNA-seq data revealed that Nsp1 broadly alters the cellular transcriptome. The cryo-EM structure of the Nsp1-40S ribosome complex shows that Nsp1 inhibits translation by plugging the mRNA-entry channel of the 40S. The team also determined the structure of the 48S preinitiation complex formed by Nsp1, 40S, and the cricket paralysis virus internal ribosome entry site (IRES) RNA, which shows that it is nonfunctional due to the incorrect position of the mRNA 3’ region. The study results elucidate the mechanism of host translation inhibition by SARS-CoV-2 and advances the understanding of the impacts from a major pathogenicity factor of SARS-CoV-2.
The study findings were published in the peer reviewed journal: Molecular Cell
Dr Yong Xiong, professor of molecular biophysics and biochemistry and co-corresponding author of the study told Thailand Medical News, "The virus essentially reprograms host cells, and by understanding this mechanism we can hopefully design new therapeutics.''
Past research had implicated a viral protein, nonstructural protein 1 or Nsp1, in the COVID-19 virus' ability to block cells' ability to produce new proteins. But exactly how NsP1 works in a cell was not known.
Utilizing advanced genetic screening and cryogenic electron microscopy (cryo-EM), the Yale research team was able to show that Nsp1 is one of SARS-CoV-2's most pathogenic viral proteins. In human lung cells, it can drastically alter host cell gene expression and essentially form a plug that prevents the ribosome, the cell's protein-making machinery, from receiving genetic instructions for new proteins encoded in messenger RNA.
Dr Xiong explained, "This is the entry channel for genetic material, and when it is blocked no protein can be made. We didn't understand this mechanism before, but now we know."
He said that this process affects protein production in many parts of the body, and high levels of Nsp1 may help explain why some people fare poorly after infection by the virus.
The study team said that it however remains unknown how the virus is still able to produce its own proteins, using the same ribosome, to replicate in the cell after it disables the cell's ability to make normal proteins.

The study team concluded, “Our results explain how Nsp1 inhibits protein synthesis; however, how SARS CoV-2 escapes this inhibition and initiate translation of its own RNA still remains unanswered. The 5’-UTR of SARS-CoV is essential for escaping Nsp1-mediated suppression of translation. Interactions involving the viral 5’ UTR presumably result in the “unplugging” of Nsp1 from the 40S ribosome during the initiation of viral translation. In addition, the weakening of eIF3 binding to the 40S subunit is beneficial for translation initiation of some viruses. The eIF3d subunit of the eIF3 complex can be cross-linked to the mRNA in the exit channel of the 48S PIC, it has its own cap-binding activity which can replace canonical eIF4E dependent pathway and promote translation of selected cellular mRNAs. Interestingly, a recent genome-wide CRISPR screen revealed the eIF3a and eIF3d are essential for SARS-CoV-2 infection.
The requirement of the same essential initiation factors suggests that it is possible that SARS-CoV-2 may use an “IRES-like” mechanism involving eIF3 recruitment by 5’ UTR to overcome Nsp1 inhibition. Binding of 5’ UTR may cause conformational change of the 40S head leading to the latch opening, Nsp1 dissociation, viral RNA loading into mRNA binding channel and formation of the functional 80S initiation complex primed for viral protein synthesis. However, the detailed mechanisms of viral escape of Nsp1 inhibition must await for future experimental studies.”
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