ArticlemBio2026
Loss of nsp14-exonuclease activity impairs the replication, proofreading, fitness, and pathogenesis of SARS-CoV-2.
Article in mBio, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
3 citing papers in PubMed.
- Distinct modes of RNA degradation by the structurally related coronavirus and arenavirus exoribonucleases.Journal of virology · 2026Article
- Recovery of proofreading-impaired SARS-CoV-2 reveals a mutator phenotype and an ExoN activity threshold for viability.Journal of virology · 2026Article
- Recovery of proofreading-impaired SARS-CoV-2 reveals a mutator phenotype and an ExoN activity threshold for viability.bioRxiv : the preprint server for biology · 2026Article
Corrections and comments
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Authors and funding
20 authors.
Funding
Abstract
Coronaviruses (CoVs) replicate their RNA genomes with a higher degree of fidelity than other RNA viruses, a mechanism mediated by the proofreading and recombination activities of the exoribonuclease domain of replicase nonstructural protein 14 (nsp14-ExoN). Both murine hepatitis virus (MHV) and SARS-CoV tolerate nsp14-ExoN loss-of-function mutations (ExoN-) (D90A and E92A), but have impaired replication fidelity and pathogenesis; yet identical substitutions in MERS-CoV and SARS-CoV-2 have been reported to be lethal. Here, we report a saturation mutagenesis approach facilitating the recovery and analysis of several constellations of SARS-CoV-2 nsp14 ExoN-inactivating, loss-of-function substitutions, including the canonical D90A and E92A. Biochemical assays with purified WT or ExoN-nsp10-14 fusion proteins confirmed that active site substitutions abolished ExoN activity (ExoN-). SARS-CoV-2 ExoN- viruses exhibited impaired replication, RNA synthesis, and recombination, as well as decreased replication fidelity and loss of fitness IMPORTANCE: Coronaviruses (CoV) are important human pathogens causing hundreds of millions of infections and millions of deaths over the past 20 years. The study of how these viruses multiply and cause disease identifies points of attack for therapeutics. Using a high-throughput genetic approach, we systematically inactivated an essential enzyme CoV needs for replication called ExoN. We show that without ExoN, CoV replication fidelity and fitness are reduced in cell culture. Replication without ExoN in mice was diminished but could be partially restored in mice that lack key components of the immune response. Altogether, we reveal new insights into the complexities of CoV replication and virus and host interactions, which could be leveraged for the development of novel multifaceted therapeutics that attack the ever-expanding functions of the CoV replication complex in replication and pathogenesis.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.