tetano
Editor, Senior Moderator
Nat Commun
. 2025 Dec 2.
doi: 10.1038/s41467-025-67001-2. Online ahead of print. SARS-CoV-2 EndoU-ribonuclease regulates RNA recombination and impacts viral fitness
Yiyang Zhou[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Yani P Ahearn[SUP] #[/SUP][SUP] 1 [/SUP], Kumari G Lokugamage[SUP] 1 2 [/SUP], Angelica L Morgan[SUP] 1 2 3 [/SUP], R Elias Alvarado[SUP] 1 [/SUP], Leah K Estes[SUP] 1 [/SUP], William M Meyers[SUP] 1 [/SUP], Alyssa M McLeland[SUP] 1 [/SUP], Jordan T Murray[SUP] 1 [/SUP], Joseph R Rouse[SUP] 2 3 [/SUP], Meenakshi Kar[SUP] 2 3 [/SUP], Mehul S Suthar[SUP] 2 3 [/SUP], David H Walker[SUP] 4 5 [/SUP], Bryan A Johnson[SUP] 1 [/SUP], Andrew L Routh[SUP] 6 [/SUP], Vineet D Menachery[SUP] 7 8 9 [/SUP]
Affiliations
Coronaviruses (CoVs) maintain large RNA genomes that frequently undergo mutations and recombination, contributing to their evolution and emergence. In this study, we find that SARS-CoV-2 has greater RNA recombination frequency than other human CoVs. In addition, CoV RNA recombination primarily occurs at uridine (U)-enriched RNA sequences. Therefore, we next evaluate the role of SARS-CoV-2 NSP15, a viral endonuclease that targets uridines (EndoU), in RNA recombination and virus infection. Using a catalytically inactivated EndoU mutant (NSP15[SUP]H234A[/SUP]), we observe attenuated viral replication in vitro and in vivo. However, the loss of EndoU activity also dysregulates inflammation resulting in similar disease in vivo despite reduced viral loads. Next-generation sequencing (NGS) demonstrates that loss of EndoU activity disrupts SARS-CoV-2 RNA recombination by reducing viral sub-genomic mRNA but increasing recombination events that contribute to defective viral genomes (DVGs). Overall, the study demonstrates that NSP15 plays a critical role in regulating RNA recombination and SARS-CoV-2 pathogenesis.
. 2025 Dec 2.
doi: 10.1038/s41467-025-67001-2. Online ahead of print. SARS-CoV-2 EndoU-ribonuclease regulates RNA recombination and impacts viral fitness
Yiyang Zhou[SUP] #[/SUP][SUP] 1 2 3 [/SUP], Yani P Ahearn[SUP] #[/SUP][SUP] 1 [/SUP], Kumari G Lokugamage[SUP] 1 2 [/SUP], Angelica L Morgan[SUP] 1 2 3 [/SUP], R Elias Alvarado[SUP] 1 [/SUP], Leah K Estes[SUP] 1 [/SUP], William M Meyers[SUP] 1 [/SUP], Alyssa M McLeland[SUP] 1 [/SUP], Jordan T Murray[SUP] 1 [/SUP], Joseph R Rouse[SUP] 2 3 [/SUP], Meenakshi Kar[SUP] 2 3 [/SUP], Mehul S Suthar[SUP] 2 3 [/SUP], David H Walker[SUP] 4 5 [/SUP], Bryan A Johnson[SUP] 1 [/SUP], Andrew L Routh[SUP] 6 [/SUP], Vineet D Menachery[SUP] 7 8 9 [/SUP]
Affiliations
- PMID: 41331255
- DOI: 10.1038/s41467-025-67001-2
Coronaviruses (CoVs) maintain large RNA genomes that frequently undergo mutations and recombination, contributing to their evolution and emergence. In this study, we find that SARS-CoV-2 has greater RNA recombination frequency than other human CoVs. In addition, CoV RNA recombination primarily occurs at uridine (U)-enriched RNA sequences. Therefore, we next evaluate the role of SARS-CoV-2 NSP15, a viral endonuclease that targets uridines (EndoU), in RNA recombination and virus infection. Using a catalytically inactivated EndoU mutant (NSP15[SUP]H234A[/SUP]), we observe attenuated viral replication in vitro and in vivo. However, the loss of EndoU activity also dysregulates inflammation resulting in similar disease in vivo despite reduced viral loads. Next-generation sequencing (NGS) demonstrates that loss of EndoU activity disrupts SARS-CoV-2 RNA recombination by reducing viral sub-genomic mRNA but increasing recombination events that contribute to defective viral genomes (DVGs). Overall, the study demonstrates that NSP15 plays a critical role in regulating RNA recombination and SARS-CoV-2 pathogenesis.