Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex

Area of Science:

• Virology
• Molecular Biology
• Gene Expression Regulation

Background:

• Viruses disrupt host gene expression for replication.
• Nuclear export of messenger RNA (mRNA) is a common viral target.
• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inhibits mRNA nuclear export.

Purpose of the Study:

• Identify novel SARS-CoV-2 inhibitors of mRNA nuclear export.
• Investigate the mechanism by which SARS-CoV-2 blocks host gene expression.
• Determine the role of viral protein Nsp14 in mRNA processing and export.

Main Methods:

• Genome-wide gene expression analysis.
• Mutation analysis of viral protein Nsp14.
• Capillary electrophoresis-mass spectrometry (CE-MS) for metabolite detection.
• Analysis of nuclear cap-binding complex (NCBC) association.

Main Results:

• Nsp14 identified as a novel inhibitor of mRNA nuclear export.
• Nsp14 causes nuclear accumulation of poly(A)+ RNA and nuclear speckle disruption.
• Nsp14 induces global splicing and 3'-end processing defects, particularly in histone mRNAs.
• Nsp14's guanine-N7-methyltransferase activity produces N7-methyl-GTP, impairing NCBC function.
• Nsp14 inhibits mRNA cap binding and recruitment of U1 snRNP and SLBP.

Conclusions:

• SARS-CoV-2 Nsp14 inhibits host mRNA processing and export.
• Nsp14's N7-methyltransferase activity generates N7-methyl-GTP, compromising NCBC function.
• This mechanism represents a novel viral strategy to suppress host gene expression.