SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome

SARS-CoV-2 is the pathogen causing the COVID-19 pandemic, that as of early February 2022 has caused 5.7 million deaths worldwide.

When a virus infects a cell, it transforms it, so it can become a “virus factory”. To do so, it needs to suspend it from doing the normal functions, but not to a point that the immune system will detect those changes and “decide” to kill the infected cell. Understanding how viruses accomplish that is very important for virology and medicine as, for example, it could be used to help the immune system identify these cells and stop the virus from spreading through the body.

To tackle this issue, researchers identify genes that get activated or repressed when a virus infects a cell. One way to monitor the genes that are “on” or “off” during the infection is to measure RNAs abundance by RNA sequencing (RNA-seq). Through this approach, recent studies showed that SARS-CoV-2 infection induces big changes on the cells that it infects. Generally, scientists believe changes induced by viral infection are the consequence of the concerned action of the virus proteins acting within the host cell. For example, the SARS-CoV-2 genome encodes 29 proteins. The effect of the virus is so strong that it changes more than 5000 genes in just 48hs, this is almost ¼ of our genes.

How do individual viral proteins contribute to these changes? To answer this question, the Kadener lab in the Department of Biology introduced singular viral SARS-CoV-2 proteins into human cells and monitored gene expression changes through RNA-seq. Between the 26 tested proteins, non-structural protein 14 (Nsp14) was the one inducing the most dramatic effect, altering the expression of ≈4000 genes. Importantly, these changes overlap well with previously published RNA-seq data from human cells infected with SARS-CoV-2. This suggests that transient expression of Nsp14 partially recapitulates the molecular events downstream to SARS-CoV-2 infection. They also showed that a cellular enzyme (IMPDH2) mediates these changes, and that treatment with IMPDH2 inhibitors partially rescues the changes induced by Nsp14.

This research contributes to understanding the function of viral proteins on the host cell and on the molecular mechanisms that control the progression of viral infection. The Kadener lab showed that Nsp14 also modulates gene expression of the host cell by activating a cellular enzyme. These events may be conserved in other coronaviruses infections and the discovery of these molecular mechanisms may be important for designing new therapeutic approaches.

Publication:

SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome. Michela Zaffagni, Jenna M Harris, Ines L Patop, Nagarjuna Reddy Pamudurti, Sinead Nguyen, Sebastian Kadener.  eLife 2022;11:e71945 DOI: 10.7554/eLife.71945.

Sebastian Kadener Returns to Brandeis as Associate Professor

From 2002 to 2008, Sebastian Kadener was a postdoc working in the Michael Rosbash laboratory. He is returning to Brandeis as an Associate Professor of Biology. Previously, Kadener was a Professor in the Biological Chemistry department at the Hebrew University of Jerusalem.

The Kadener laboratory studies how molecular processes in the brain determines behavior with a special emphasis on RNA metabolism. Additionally, they study the role of circular RNAs (circRNAs) at the molecular and neural levels as well as the mechanisms underlying circadian clocks.

Kadener’s paper, “Translation of CircRNAs”, appeared in Molecular Cell in April 2017. It was reviewed in Nature Reviews Genetics and Science Daily.