| RRC ID |
81714
|
| Author |
Katahira J, Ohmae T, Yasugi M, Sasaki R, Itoh Y, Kohda T, Hieda M, Yokota Hirai M, Okamoto T, Miyamoto Y.
|
| Title |
Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex.
|
| Journal |
Nucleic Acids Res
|
| Abstract |
To facilitate selfish replication, viruses halt host gene expression in various ways. The nuclear export of mRNA is one such process targeted by many viruses. SARS-CoV-2, the etiological agent of severe acute respiratory syndrome, also prevents mRNA nuclear export. In this study, Nsp14, a bifunctional viral replicase subunit, was identified as a novel inhibitor of mRNA nuclear export. Nsp14 induces poly(A)+ RNA nuclear accumulation and the dissolution/coalescence of nuclear speckles. Genome-wide gene expression analysis revealed the global dysregulation of splicing and 3'-end processing defects of replication-dependent histone mRNAs by Nsp14. These abnormalities were also observed in SARS-CoV-2-infected cells. A mutation introduced at the guanine-N7-methyltransferase active site of Nsp14 diminished these inhibitory activities. Targeted capillary electrophoresis-mass spectrometry analysis (CE-MS) unveiled the production of N7-methyl-GTP in Nsp14-expressing cells. Association of the nuclear cap-binding complex (NCBC) with the mRNA cap and subsequent recruitment of U1 snRNP and the stem-loop binding protein (SLBP) were impaired by Nsp14. These data suggest that the defects in mRNA processing and export arise from the compromise of NCBC function by N7-methyl-GTP, thus exemplifying a novel viral strategy to block host gene expression.
|
| Volume |
51(14)
|
| Pages |
7602-7618
|
| Published |
2023-8-11
|
| DOI |
10.1093/nar/gkad483
|
| PII |
7187708
|
| PMID |
37260089
|
| PMC |
PMC10415132
|
| MeSH |
Active Transport, Cell Nucleus*
COVID-19* / virology
Exoribonucleases / metabolism
Guanosine Triphosphate / metabolism
Humans
RNA, Messenger* / metabolism
RNA, Viral / genetics
RNA, Viral / metabolism
SARS-CoV-2* / metabolism
Viral Nonstructural Proteins* / metabolism
|
| Resource |
| DNA material |
pENTR4-GFP-Nsp14-BGHpA (RDB20274)
pCMV-FLAG3-DcpS (RDB20275)
pENTR4-GFP-DcpS-BGHpA (RDB20276) |
