TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence.
Jiang RenShuai WangZhi ZongTing PanSijia LiuWei MaoHuizhe HuangXiaohua YanBing YangXin HeFangfang ZhouJisheng LiuPublished in: Nature communications (2024)
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.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- immune response
- escherichia coli
- pseudomonas aeruginosa
- staphylococcus aureus
- antimicrobial resistance
- dendritic cells
- drug delivery
- cell proliferation
- machine learning
- inflammatory response
- coronavirus disease
- data analysis
- cell cycle arrest
- signaling pathway
- reactive oxygen species
- quantum dots
- candida albicans