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    Home > Active Ingredient News > Immunology News > STTT: Cui Jun/Zhao Jincun et al. Reveal a new mechanism for the new crown nucleocapsid protein to promote host inflammatory response through phase change

    STTT: Cui Jun/Zhao Jincun et al. Reveal a new mechanism for the new crown nucleocapsid protein to promote host inflammatory response through phase change

    • Last Update: 2021-05-22
    • Source: Internet
    • Author: User
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    The new crown pneumonia (COVID-19) epidemic caused by the new crown virus (SARS-CoV-2) is still raging around the world.

    Studies have shown that the abnormal inflammatory response caused by the virus is closely related to the progression of COVID-19 disease.

    In the process of virus infection, the virus induces the body's immune system to produce chemokines and inflammatory factors, and recruit immune cells to eliminate the virus.

    In some patients, the virus-mediated immune response will be over-activated, leading to severe inflammatory reactions and generating "inflammatory factor storms", causing tissue damage, multiple organ failure, and even patient death.

    Therefore, exploring the pathway and mechanism of excessive inflammation caused by the new coronavirus, and using this as a basis to reduce the inflammatory response caused by the new coronavirus, is expected to improve the clinical prognosis of patients.

    However, the specific molecular mechanism that activates the host's inflammatory response during the new coronavirus infection is currently unclear.

     Nucleocapsid (N) protein is the most abundant and conserved protein in coronaviruses, and it is the core component of virus particles.

    The N protein can not only recognize viral RNA and package it into a ribonucleoprotein (RNP) complex, but also participate in multiple processes such as viral transcription, replication, and immune regulation by binding to the virus or host protein.

    Recently, a number of research groups at home and abroad have discovered that the new coronavirus N protein can form a "liquid-liquid phase separation" phenomenon with viral RNA.

    "Liquid-liquid" phase separation (LLPS) is a new concept that has rapidly developed in the field of life sciences.

    Under certain conditions, the biological macromolecules in the solution will be highly aggregated and concentrated due to the interaction, separated from the ordinary solution phase, and form an independent and viscous liquid phase (LLPS droplets).

    The phase separation of biological macromolecules is considered to be an important mechanism that mediates the formation of membraneless organelles and membraneless particles in cells.

    LLPS has been found to be involved in many key cellular processes such as gene regulation, signal transduction, and stress response, and has quickly become the research frontier in the field of life sciences.

    So does the LLPS formed by the N protein of the new coronavirus participate in the virus-mediated inflammatory response process? Recently, Professor Jun Cui’s team from the School of Life Sciences, Sun Yat-sen University and Professor Jincun Zhao’s team from the State Key Laboratory of Respiratory Diseases of Guangzhou Medical University published the title: RNA-induced liquid phase separation of SARS-CoV-2 in the journal Signal Transduction and Targeted Therapy.
    nucleocapsid protein facilitates research papers on NF-κB hyper-activation and inflammation.

    Based on the combination of the new coronavirus N protein and viral RNA to form a "liquid-liquid phase separation" (LLPS), this study further explored the relationship between the new coronavirus N protein LLPS and the host's inflammatory response, and revealed that the new coronavirus uses the N protein LLPS Promote the overactivation of the host NF-κB pathway and the molecular mechanism of inflammation.

     Previously, the research results of Professor Cui Jun's team and different teams at home and abroad have shown that multiple proteins in the new coronavirus are involved in suppressing the host's innate immune response.

    This study found that, unlike previous viral proteins that negatively regulate host immunity, the N protein of the new coronavirus can promote the host's inflammatory response in the late stage of viral infection, which may be related to the cytokine storm caused by the new coronavirus.

    Further mechanism studies have shown that the new coronavirus N protein can recruit the key kinases TAK1 and IKKβ in the NF-κB pathway, promote the interaction between TAK1 and IKKβ, and activate IKKβ phosphorylation.

    By promoting the combination of TAK1 and IKKβ, the N protein promotes the activation of the host NF-κB pathway and induces cells to secrete a large number of pro-inflammatory cytokines, including IL-6, IL-1β, IL-8 and TNFα.

     Further studies have shown that the N protein of the new coronavirus can bind to single-stranded and double-stranded RNA of the virus and form "liquid-liquid separation aggregates.
    "
    Intracellular and in vitro remodeling experiments showed that viral RNA-N protein phase separation aggregates can recruit TAK1 and IKKβ, and bring TAK1 and IKKβ into RNA-N protein aggregates.

    The phase separation of RNA-N protein has a certain selectivity.
    RNA-N protein can bring TAK1 into the phase-separated aggregate to form an activated core, and at the same time bind IKKβ to the periphery of the phase-separated droplet to form a special outer ring structure.
    This structure may increase the binding area of ​​IKKβ and downstream molecules, and enhance the kinase activity of IKKβ.

    In addition, treatment with 1,6 hexanediol (LLPS inhibitor) inhibits the formation of N protein phase separation, which not only weakens the interaction between TAK1 and IKKβ during viral infection, but also inhibits the inflammatory response and the release of inflammatory factors inhibited by neocoronavirus infection.

    The new coronavirus nucleocapsid (N) protein recruits TAK1 and IKKβ through the formation of LLPS to promote the excessive activation of the host NF-κB pathway: ab, purification of the new coronavirus N protein, TAK1 and IKKβ, in vitro reconstruction phase separation system; c, intracellular new coronavirus The N protein promotes the formation of "LLPS droplets" between TAK1 and IKKβ; d, the schematic diagram of the mechanism of the new coronavirus N protein promoting the NF-κB pathway through LLPS.

     In summary, the study found that the new coronavirus and the encoded N protein promote the host NF-κB pathway and inflammatory response, revealing that the N protein recruits the key NF-κB kinases TAK1 and IKKβ through LLPS and forms a phase-separated complex The molecular mechanism of new coronary pneumonia, and proposes a new anti-inflammatory strategy of targeted phase separation for the treatment of new coronary pneumonia.

     Professor Cui Jun, School of Life Sciences, Sun Yat-sen University, and Professor Zhao Jincun, State Key Laboratory of Respiratory Diseases, Guangzhou Medical University, are the co-corresponding authors of this work.

    Associate researcher Wu Yaoxing, Dr.
    Ma Ling, and Master Cai Sihui from the School of Life Sciences, Sun Yat-sen University, and Dr.
    Zhuang Zhen from the State Key Laboratory of Respiratory Diseases of Guangzhou Medical University are the co-first authors of the paper.

    The research was funded by the National Key Basic Research and Development Program, the National Natural Science Foundation of China and other projects.

    Link to the paper: Open for reprint 
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