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

作者全名："Ren, Jiang; Wang, Shuai; Zong, Zhi; Pan, Ting; Liu, Sijia; Mao, Wei; Huang, Huizhe; Yan, Xiaohua; Yang, Bing; He, Xin; Zhou, Fangfang; Zhang, Long"

作者地址："[Ren, Jiang; Zhang, Long] Sun Yat Sen Univ, Affiliated Hosp 8, Shenzhen 518033, Peoples R China; [Wang, Shuai; Zhou, Fangfang] Soochow Univ, Inst Biol & Med Sci, Suzhou 215123, Peoples R China; [Zong, Zhi; Yang, Bing; Zhang, Long] Zhejiang Univ, MOE Key Lab Biosyst Homeostasis & Protect, Hangzhou 310058, Peoples R China; [Zong, Zhi; Yang, Bing; Zhang, Long] Zhejiang Univ, Life Sci Inst, Innovat Ctr Cell Signaling Network, Hangzhou 310058, Peoples R China; [Pan, Ting] Sun Yat Sen Univ, Sch Med, Shenzhen Key Lab Syst Med Inflammatory Dis, Shenzhen Campus, Shenzhen 518107, Peoples R China; [Liu, Sijia] Zhejiang Univ, Sch Med, Int Biomed X Res Ctr, Affiliated Hosp 2, Hangzhou 310058, Peoples R China; [Mao, Wei] Zhejiang Univ, Zhejiang Hosp, Dept Genet, Sch Med, Hangzhou 310058, Peoples R China; [Huang, Huizhe] Chongqing Med Univ, Fac Basic Med Sci, Chongqing 400016, Peoples R China; [Yan, Xiaohua] Nanchang Univ, Sch Basic Med Sci, Dept Biochem & Mol Biol, Nanchang 330031, Peoples R China; [Yang, Bing] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA; [Yang, Bing] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA; [He, Xin] Sun Yat Sen Univ, Inst Human Virol, Zhongshan Sch Med, Guangzhou 510080, Guangdong, Peoples R China"

通信作者："Zhang, L (通讯作者)，Sun Yat Sen Univ, Affiliated Hosp 8, Shenzhen 518033, Peoples R China.; Zhou, FF (通讯作者)，Soochow Univ, Inst Biol & Med Sci, Suzhou 215123, Peoples R China.; Zhang, L (通讯作者)，Zhejiang Univ, MOE Key Lab Biosyst Homeostasis & Protect, Hangzhou 310058, Peoples R China.; Zhang, L (通讯作者)，Zhejiang Univ, Life Sci Inst, Innovat Ctr Cell Signaling Network, Hangzhou 310058, Peoples R China.; He, X (通讯作者)，Sun Yat Sen Univ, Inst Human Virol, Zhongshan Sch Med, Guangzhou 510080, Guangdong, Peoples R China."

来源：NATURE COMMUNICATIONS

ESI学科分类：　

WOS号：WOS:001136406000008

JCR分区：Q1

影响因子：16.6

年份：2024

卷号：15

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："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."

基金机构："Ministry of Science and Technology of China [2021YFA1101000, 2022YFA1105200]; Chinese National Natural Science Funds [U20A20393, 31925013, 32125016, 32070907, 32200575, 31771619, 22074132]; Zhejiang Natural Science Fund [LD19C070001]; Suzhou Medical College Basic Frontier Innovation Cross Project [YXY2303027]; Suzhou Innovation and Entrepreneurship Leading Talent Program [ZXL2022505]; Key Cross-research Projects of the School of Medicine, Soochow University [YXY2303027]; Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases [20230206]; Soochow University, Zhejiang University School of Medicine; Life Sciences Institute"

基金资助正文："The current work was supported by a special program from the Ministry of Science and Technology of China (2021YFA1101000, 2022YFA1105200), the Chinese National Natural Science Funds (U20A20393, 31925013, 32125016, 32070907, 32200575, 31771619, and 22074132), the Zhejiang Natural Science Fund (LD19C070001), Suzhou Medical College Basic Frontier Innovation Cross Project (YXY2303027), Suzhou Innovation and Entrepreneurship Leading Talent Program (ZXL2022505), Key Cross-research Projects of the School of Medicine, Soochow University (YXY2303027), Suzhou International Joint Laboratory for Diagnosis and Treatment of Brain Diseases, and Special Scientific and Technological Project for Emergency Treatment of Novel Coronavirus Infection with Traditional Chinese Medicine jointly funded by the National Administration of Traditional Chinese Medicine and Zhejiang Province (20230206). Additionally, we acknowledge the support from the platform of Sun Yat-sen University, Soochow University, Zhejiang University School of Medicine and the Life Sciences Institute."