IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-023-44502-6.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    University of California)

  • Xin He

    (Sun Yat-sen University)

  • Fangfang Zhou

    (Soochow University)

  • Long Zhang

    (Sun Yat-sen University
    Zhejiang University)

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.

Suggested Citation

  • Jiang Ren & Shuai Wang & Zhi Zong & Ting Pan & Sijia Liu & Wei Mao & Huizhe Huang & Xiaohua Yan & Bing Yang & Xin He & Fangfang Zhou & Long Zhang, 2024. "TRIM28-mediated nucleocapsid protein SUMOylation enhances SARS-CoV-2 virulence," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44502-6
    DOI: 10.1038/s41467-023-44502-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-44502-6
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-44502-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Lingjie Yan & Tao Zhang & Kai Wang & Zezhao Chen & Yuanxin Yang & Bing Shan & Qi Sun & Mengmeng Zhang & Yichi Zhang & Yedan Zhong & Nan Liu & Jinyang Gu & Daichao Xu, 2022. "SENP1 prevents steatohepatitis by suppressing RIPK1-driven apoptosis and inflammation," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    2. Shan Lu & Qiaozhen Ye & Digvijay Singh & Yong Cao & Jolene K. Diedrich & John R. Yates & Elizabeth Villa & Don W. Cleveland & Kevin D. Corbett, 2021. "The SARS-CoV-2 nucleocapsid phosphoprotein forms mutually exclusive condensates with RNA and the membrane-associated M protein," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Ming Zhao & Yu Yu & Li-Ming Sun & Jia-Qing Xing & Tingting Li & Yunkai Zhu & Miao Wang & Yin Yu & Wen Xue & Tian Xia & Hong Cai & Qiu-Ying Han & Xiaoyao Yin & Wei-Hua Li & Ai-Ling Li & Jiuwei Cui & Zh, 2021. "GCG inhibits SARS-CoV-2 replication by disrupting the liquid phase condensation of its nucleocapsid protein," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    4. Christoph J. Wienken & Philipp Baaske & Ulrich Rothbauer & Dieter Braun & Stefan Duhr, 2010. "Protein-binding assays in biological liquids using microscale thermophoresis," Nature Communications, Nature, vol. 1(1), pages 1-7, December.
    5. Jovan Nikolic & Romain Le Bars & Zoé Lama & Nathalie Scrima & Cécile Lagaudrière-Gesbert & Yves Gaudin & Danielle Blondel, 2017. "Negri bodies are viral factories with properties of liquid organelles," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
    6. Adriana Savastano & Alain Ibáñez de Opakua & Marija Rankovic & Markus Zweckstetter, 2020. "Nucleocapsid protein of SARS-CoV-2 phase separates into RNA-rich polymerase-containing condensates," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Sophie Marianne Korn & Karthikeyan Dhamotharan & Cy M. Jeffries & Andreas Schlundt, 2023. "The preference signature of the SARS-CoV-2 Nucleocapsid NTD for its 5’-genomic RNA elements," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Einav Tayeb-Fligelman & Jeannette T. Bowler & Christen E. Tai & Michael R. Sawaya & Yi Xiao Jiang & Gustavo Garcia & Sarah L. Griner & Xinyi Cheng & Lukasz Salwinski & Liisa Lutter & Paul M. Seidler &, 2023. "Low complexity domains of the nucleocapsid protein of SARS-CoV-2 form amyloid fibrils," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Mirren Charnley & Saba Islam & Guneet K. Bindra & Jeremy Engwirda & Julian Ratcliffe & Jiangtao Zhou & Raffaele Mezzenga & Mark D. Hulett & Kyunghoon Han & Joshua T. Berryman & Nicholas P. Reynolds, 2022. "Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. Naijun Miao & Zhuning Wang & Qinlan Wang & Hongyan Xie & Ninghao Yang & Yanzhe Wang & Jin Wang & Haixia Kang & Wenjuan Bai & Yuanyuan Wang & Rui He & Kepeng Yan & Yang Wang & Qiongyi Hu & Zhaoyuan Liu, 2023. "Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    5. Georg Krainer & Kadi L. Saar & William E. Arter & Timothy J. Welsh & Magdalena A. Czekalska & Raphaël P. B. Jacquat & Quentin Peter & Walther C. Traberg & Arvind Pujari & Akhila K. Jayaram & Pavankuma, 2023. "Direct digital sensing of protein biomarkers in solution," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    6. Jingru Fang & Guillaume Castillon & Sebastien Phan & Sara McArdle & Chitra Hariharan & Aiyana Adams & Mark H. Ellisman & Ashok A. Deniz & Erica Ollmann Saphire, 2023. "Spatial and functional arrangement of Ebola virus polymerase inside phase-separated viral factories," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    7. William E. Arter & Runzhang Qi & Nadia A. Erkamp & Georg Krainer & Kieran Didi & Timothy J. Welsh & Julia Acker & Jonathan Nixon-Abell & Seema Qamar & Jordina Guillén-Boixet & Titus M. Franzmann & Dav, 2022. "Biomolecular condensate phase diagrams with a combinatorial microdroplet platform," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    8. Bing Han & Zhan-Ming Li & Xu-Yun Zhao & Kai Liang & Yu-Qin Mao & Shi-Long Zhang & Li-Ying Huang & Chao-Yue Kong & Xin Peng & Hui-Ling Chen & Jia-Ting Huang & Zhao-Xia Wu & Jin-Qing Yao & Pei-Ran Cai &, 2024. "Annonaceous acetogenins mimic AA005 targets mitochondrial trifunctional enzyme alpha subunit to treat obesity in male mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    9. Cheng Peng & Yuanna Cheng & Mingtong Ma & Qiu Chen & Yongjia Duan & Shanshan Liu & Hongyu Cheng & Hua Yang & Jingping Huang & Wenyi Bu & Chenyue Shi & Xiangyang Wu & Jianxia Chen & Ruijuan Zheng & Zho, 2024. "Mycobacterium tuberculosis suppresses host antimicrobial peptides by dehydrogenating L-alanine," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    10. Yejinpeng Wang & Lingao Ju & Gang Wang & Kaiyu Qian & Wan Jin & Mingxing Li & Jingtian Yu & Yiliang Shi & Yongzhi Wang & Yi Zhang & Yu Xiao & Xinghuan Wang, 2023. "DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    11. Yuan Lin & Theresa A. Ramelot & Simge Senyuz & Attila Gursoy & Hyunbum Jang & Ruth Nussinov & Ozlem Keskin & Yi Zheng, 2024. "Tumor-derived RHOA mutants interact with effectors in the GDP-bound state," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    12. Emilie Murigneux & Laurent Softic & Corentin Aubé & Carmen Grandi & Delphine Judith & Johanna Bruce & Morgane Le Gall & François Guillonneau & Alain Schmitt & Vincent Parissi & Clarisse Berlioz-Torren, 2024. "Proteomic analysis of SARS-CoV-2 particles unveils a key role of G3BP proteins in viral assembly," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    13. Yumin Wang & Boya Gao & Luyuan Zhang & Xudong Wang & Xiaolan Zhu & Haibo Yang & Fengqi Zhang & Xueping Zhu & Badi Zhou & Sean Yao & Aiko Nagayama & Sanghoon Lee & Jian Ouyang & Siang-Boon Koh & Eric L, 2024. "Meiotic protein SYCP2 confers resistance to DNA-damaging agents through R-loop-mediated DNA repair," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    14. Yunxi Liu & Nicolae Sapoval & Pilar Gallego-García & Laura Tomás & David Posada & Todd J. Treangen & Lauren B. Stadler, 2024. "Crykey: Rapid identification of SARS-CoV-2 cryptic mutations in wastewater," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    15. Laura Czech & Christopher-Nils Mais & Hanna Kratzat & Pinku Sarmah & Pietro Giammarinaro & Sven-Andreas Freibert & Hanna Folke Esser & Joanna Musial & Otto Berninghausen & Wieland Steinchen & Roland B, 2022. "Inhibition of SRP-dependent protein secretion by the bacterial alarmone (p)ppGpp," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    16. Zhikuan Zhang & Norimichi Nomura & Yukiko Muramoto & Toru Ekimoto & Tomoko Uemura & Kehong Liu & Moeko Yui & Nozomu Kono & Junken Aoki & Mitsunori Ikeguchi & Takeshi Noda & So Iwata & Umeharu Ohto & T, 2022. "Structure of SARS-CoV-2 membrane protein essential for virus assembly," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    17. Noha A. M. Shendy & Melissa Bikowitz & Logan H. Sigua & Yang Zhang & Audrey Mercier & Yousef Khashana & Stephanie Nance & Qi Liu & Ian M. Delahunty & Sarah Robinson & Vanshita Goel & Matthew G. Rees &, 2024. "Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    18. Shuqi Xu & Alice J. Hutchinson & Mahdiar Taheri & Ben Corry & Juan F. Torres, 2024. "Thermodiffusive desalination," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    19. Motohiro Sekiya & Kenta Kainoh & Takehito Sugasawa & Ryunosuke Yoshino & Takatsugu Hirokawa & Hiroaki Tokiwa & Shogo Nakano & Satoru Nagatoishi & Kouhei Tsumoto & Yoshinori Takeuchi & Takafumi Miyamot, 2021. "The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis," Nature Communications, Nature, vol. 12(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44502-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.