| First Authors | Theresia Gutmann, David Kuster |
|---|---|
| Authors | Theresia Gutmann, David Kuster, Anthony Hyman |
| Corresponding Authors | Theresia Gutmann, Anthony Hyman |
| Last Authors | Anthony Hyman |
| Journal Name | Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U.S.A.) |
| Volume | 122 |
| Issue | 26 |
| Article Number | doi: 10.1073/pnas.2426204122 |
| Open Access | true |
| Print Publication Date | 2025-07-01 |
| Online Publication Date | 2025-07-01 |
| Abstract | A hallmark of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the delayed interferon response. Interferons are typically produced upon host recognition of pathogen- or damage-associated molecular patterns, such as nucleic acids. While the mechanisms by which SARS-CoV-2 evades host recognition of its RNA are well studied, how it evades immune responses to cytosolic DNA-leaked from mitochondria or nuclei during infection-remains poorly understood. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein directly suppresses DNA sensing by cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS). Although primarily known for packaging the viral RNA genome, we uncover that the SARS-CoV-2 nucleocapsid protein also binds DNA with high affinity and competitively blocks cGAS activation. Using cell-free biochemical and biophysical approaches, including single-molecule optical tweezers, we show that the nucleocapsid protein binds to DNA at nanomolar concentrations and cocondenses with DNA at micromolar concentrations, thereby impeding stable cGAS-DNA interactions required for signal propagation. Hyperphosphorylation of the nucleocapsid protein diminishes its competitive binding capacity. Our findings reveal an unexpected role of the SARS-CoV-2 nucleocapsid protein in directly suppressing the cGAS-STING pathway, strongly suggesting that this contributes to the delayed interferon response during infection. This study raises the possibility that nucleocapsid proteins of other RNA viruses may also exhibit moonlighting functions by antagonizing host nucleic acid-sensing pathways. |
| Cover Image | |
| Affiliated With | Hyman, Postdoc first author, Postdoc first female, Postdocs, Predoc first author, Predoc first male |
| Selected By | |
| Acknowledged Services | Biophysics Core Facility, Protein Expression, Light Microscopy Facility, Scientific Infrastructure |
| Publication Status | Published |
| Edoc Link | |
| Sfx Link | |
| DOI | 10.1073/pnas.2426204122 |
| PubMed ID | 40549905 |
| WebOfScience Link | |
| Alternative Full Text URL | |
| Display Publisher Download Only | false |
| Visible On MPI-CBG Website | true |
| PDF Downloadable | true |
| Created By | thuem |
| Added Date | 2025-06-25 |
| Last Edited By | thuem |
| Last Edited Date | 2025-06-26 09:15:36.46 |
| Library ID | 9017 |
| Document ID | |
| Entry Complete | true |
| eDoc Compliant | true |
| Include in Edoc Report | true |
| In Pure | false |
| Ready for eDoc Export | false |
| Author Affiliations Complete | false |
| Project Name | |
| Project URL | |
| Grant ID | |
| Funding Programme | |
| Funding Organisation |