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- Title
TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence.
- Authors
Ren, Jiang; Wang, Shuai; Zong, Zhi; Pan, Ting; Liu, Sijia; Mao, Wei; Huang, Huizhe; Yan, Xiaohua; Yang, Bing; He, Xin; Zhou, Fangfang; Zhang, Long
- Abstract
Viruses, as opportunistic intracellular parasites, hijack the cellular machinery of host cells to support their survival and propagation. Numerous viral proteins are subjected to host-mediated post-translational modifications. Here, we demonstrate that the SARS-CoV-2 nucleocapsid protein (SARS2-NP) is SUMOylated on the lysine 65 residue, which efficiently mediates SARS2-NP's ability in homo-oligomerization, RNA association, liquid-liquid phase separation (LLPS). Thereby the innate antiviral immune response is suppressed robustly. These roles can be achieved through intermolecular association between SUMO conjugation and a newly identified SUMO-interacting motif in SARS2-NP. Importantly, the widespread SARS2-NP R203K mutation gains a novel site of SUMOylation which further increases SARS2-NP's LLPS and immunosuppression. Notably, the SUMO E3 ligase TRIM28 is responsible for catalyzing SARS2-NP SUMOylation. An interfering peptide targeting the TRIM28 and SARS2-NP interaction was screened out to block SARS2-NP SUMOylation and LLPS, and consequently inhibit SARS-CoV-2 replication and rescue innate antiviral immunity. Collectively, these data support SARS2-NP SUMOylation is critical for SARS-CoV-2 virulence, and therefore provide a strategy to antagonize SARS-CoV-2. Here, the authors show that TRIM28-mediated SUMOylation of SARS-CoV-2 NP is critical for its liquid-liquid phase separation (LLPS) property and subsequent inhibition of innate antiviral immunity. The peptide NSIP-III is applied to unleash such connection by interfering TRIM28 and NP interaction.
- Subjects
SARS-CoV-2; POST-translational modification; PEPTIDES; PHASE separation; INTRACELLULAR pathogens
- Publication
Nature Communications, 2024, Vol 15, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-44502-6