TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence

Jiang Ren, Shuai Wang, Zhi Zong, Ting Pan, Sijia Liu, Wei Mao, Huizhe Huang, Xiaohua Yan, Bing Yang, Xin He (), Fangfang Zhou () and Long Zhang ()
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Jiang Ren: Sun Yat-sen University
Shuai Wang: Soochow University
Zhi Zong: Zhejiang University
Ting Pan: Shenzhen Campus of Sun Yat-sen University
Sijia Liu: Zhejiang University School of Medicine
Wei Mao: Zhejiang University School of Medicine
Huizhe Huang: Chongqing Medical University
Xiaohua Yan: Nanchang University
Bing Yang: Zhejiang University
Xin He: Sun Yat-sen University
Fangfang Zhou: Soochow University
Long Zhang: Sun Yat-sen University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-023-44502-6

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