SARS-CoV-2 rewires host proteins to promote infection
By Samantha Black, PhD, The Science Advisory Board
June 30, 2020
To successfully infect human cells, SARS-CoV-2 may hijack host proteins in target cells to promote its own replication. Researchers may be able to leverage this information to identify and recommend drugs, according to a June 29 Cell article.
Viruses are unable to replicate and spread on their own, and instead must take control of a host cell's machinery and manipulate it to support viral replication and infection. Sometimes, this occurs by modifying host proteins, whereby chemical modifications can alter their structure and function.
One example of this process is phosphorylation -- the addition of a phosphoryl group to a protein by kinase enzymes. Kinases are key regulatory enzymes that play an essential role in many cell processes. Altering phosphorylation patterns of host proteins by viruses can potentially promote viral replication and transmission to other hosts.
According to the international team of researchers, proteomics approaches can offer a powerful way to quantify global changes in protein abundance and phosphorylation to elucidate mechanisms of viral pathogenesis, specifically by providing insight into how cellular pathways and processes are rewired upon infection.
The power of phosphoproteomics analysis for COVID-19
In the current study, the team used a mass spectrometry approach to study changes in protein abundance and phosphorylation during SARS-CoV-2 infection. Large changes in protein phosphorylation were observed within 24 hours of infection, indicating that the virus makes use of host post-translational regulatory systems to promote changes in cellular signaling. They found that 12% of host proteins that interact with the virus were modified.
The researchers suggest that kinases are hijacked during infection and most likely regulate the modifications of host proteins. Based on the phosphoproteomics survey, 97 of the 518 human kinases measured were changed by infection. Elevated p38 mitogen-activated protein kinase (MAPK) and casein kinase II (CK2) activation suggests that the virus induces changes in cytoskeleton organization of host cells.
The researchers observed that an increase in p38/MAPK signaling pathway activity occurred late in the time course, likely reflecting a more advanced stage of infection. The p38/MAPK pathway controls the production of potentially harmful pro-inflammatory cytokines, which is also observed in SARS-CoV-2 infection. However, the specific impact of p38/MAPK inhibition during SARS-CoV-2 remains unknown.
Alternatively, upregulated CK2 activation, in combination with reduced activity of cyclin dependent kinase (CDK1/2) activity during SARS-CoV-2 infection, led to a synthesis/gap 2 phase arrest, which may benefit the virus by ensuring its abundant supply of nucleotides and other essential host DNA proteins.
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