Nsp1 protein of SARS-CoV-2 disrupts the mRNA export machinery to inhibit host gene expression
Ke Zhang, Lisa Miorin, Tadashi Makio, Ishmael Dehghan, Shengyan Gao, Yihu Xie, Hualin Zhong, Matthew A. Esparza, Thomas Kehrer, Anil Kumar, Tom C. Hobman, Christopher P. Ptak, Boning Gao, John D. Minna, Zhijian J. Chen, Adolfo García‐Sastre, Yi Ren, Richard W. Wozniak, Beatriz M. A. Fontoura
Abstract
The ongoing unprecedented severe acute respiratory syndrome caused by the SARS-CoV-2 outbreak worldwide has highlighted the need for understanding viral-host interactions involved in mechanisms of virulence. Here, we show that the virulence factor Nsp1 protein of SARS-CoV-2 interacts with the host messenger RNA (mRNA) export receptor heterodimer NXF1-NXT1, which is responsible for nuclear export of cellular mRNAs. Nsp1 prevents proper binding of NXF1 to mRNA export adaptors and NXF1 docking at the nuclear pore complex. As a result, a significant number of cellular mRNAs are retained in the nucleus during infection. Increased levels of NXF1 rescues the Nsp1-mediated mRNA export block and inhibits SARS-CoV-2 infection. Thus, antagonizing the Nsp1 inhibitory function on mRNA export may represent a strategy to restoring proper antiviral host gene expression in infected cells.