SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.
SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.
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DOI：
10.1073/pnas.2204539119
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发表时间：
2022-08-09
影响因子：
11.1
通讯作者：
Sonenberg, Nahum
中科院分区：
文献类型：
--
作者：
Xu, Zhang;Choi, Jung-Hyun;Dai, David L.;Luo, Jun;Ladak, Reese Jalal;Li, Qian;Wang, Yimeng;Zhang, Christine;Wiebe, Shane;Liu, Alex C. H.;Ran, Xiaozhuo;Yang, Jiaqi;Naeli, Parisa;Garzia, Aitor;Zhou, Lele;Mahmood, Niaz;Deng, Qiyun;Elaish, Mohamed;Lin, Rongtuan;Mahal, Lara K.;Hobman, Tom C.;Pelletier, Jerry;Alain, Tommy;Vidal, Silvia M.;Duchaine, Thomas;Mazhab-Jafari, Mohammad T.;Mao, Xiaojuan;Jafarnejad, Seyed Mehdi;Sonenberg, Nahum
强大的抗病毒先天免疫反应是对抗感染不可或缺的。然而，加剧的反应可导致病理性炎症和组织损伤。mRNA翻译控制机制在维持免疫反应的适当程度和持续时间方面起着至关重要的作用。我们发现GIGYF2/4EHP翻译抑制复合体抑制编码I型干扰素β (IFN-β)的Ifnb1 mRNA的翻译。我们还证明了SARS-CoV-2病毒编码的NSP2蛋白通过选择GIGYF2/4EHP复合体进一步阻碍Ifnb1 mRNA的翻译，从而导致逃避细胞先天免疫反应。了解nsp2介导的IFN-β抑制的作用机制为开发SARS-CoV-2和其他冠状病毒感染的治疗方法提供了有价值的信息。病毒通过抑制I型干扰素（ifn）等细胞因子的产生或活性来逃避先天免疫反应。在这里，我们报告了SARS-CoV-2病毒利用内在细胞机制抑制关键免疫刺激细胞因子IFN-β产生的机制。我们发现SARS-CoV-2编码的非结构蛋白2 （NSP2）直接与细胞GIGYF2蛋白相互作用。这种相互作用增强了GIGYF2与mRNA帽结合蛋白4EHP的结合，从而抑制了Ifnb1 mRNA的翻译。耗尽GIGYF2或4EHP可显著提高IFN-β的产生，从而抑制SARS-CoV-2的复制。我们的研究结果揭示了拯救针对SARS-CoV-2和其他RNA病毒的抗病毒先天免疫反应的靶标。
A robust antiviral innate immune response is indispensable for combating infections. However, an exacerbated response can result in pathological inflammation and tissue damage. mRNA translational control mechanisms play a crucial role in maintaining the appropriate magnitude and duration of the immune response. We show that the GIGYF2/4EHP translational repressor complex represses translation of Ifnb1 mRNA, which encodes type I interferon β (IFN-β). We also demonstrate that the NSP2 protein encoded by SARS-CoV-2 virus further impedes translation of Ifnb1 mRNA through coopting the GIGYF2/4EHP complex, leading to evasion of a cellular innate immune response. The knowledge of the mechanism of action of NSP2-mediated IFN-β suppression provides valuable information for development of treatments for infections of SARS-CoV-2 and other coronaviruses. Viruses evade the innate immune response by suppressing the production or activity of cytokines such as type I interferons (IFNs). Here we report the discovery of a mechanism by which the SARS-CoV-2 virus coopts an intrinsic cellular machinery to suppress the production of the key immunostimulatory cytokine IFN-β. We reveal that the SARS-CoV-2 encoded nonstructural protein 2 (NSP2) directly interacts with the cellular GIGYF2 protein. This interaction enhances the binding of GIGYF2 to the mRNA cap-binding protein 4EHP, thereby repressing the translation of the Ifnb1 mRNA. Depletion of GIGYF2 or 4EHP significantly enhances IFN-β production, which inhibits SARS-CoV-2 replication. Our findings reveal a target for rescuing the antiviral innate immune response to SARS-CoV-2 and other RNA viruses.
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影响因子：
4.6
作者：
Masood KI;Yameen M;Ashraf J;Shahid S;Mahmood SF;Nasir A;Nasir N;Jamil B;Ghanchi NK;Khanum I;Razzak SA;Kanji A;Hussain R;E Rottenberg M;Hasan Z
通讯作者：
Hasan Z
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
危及生命的Covid-19患者中针对I型IFN的自身抗体。
DOI：
10.1126/science.abd4585
发表时间：
2020-10-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bastard P;Rosen LB;Zhang Q;Michailidis E;Hoffmann HH;Zhang Y;Dorgham K;Philippot Q;Rosain J;Béziat V;Manry J;Shaw E;Haljasmägi L;Peterson P;Lorenzo L;Bizien L;Trouillet-Assant S;Dobbs K;de Jesus AA;Belot A;Kallaste A;Catherinot E;Tandjaoui-Lambiotte Y;Le Pen J;Kerner G;Bigio B;Seeleuthner Y;Yang R;Bolze A;Spaan AN;Delmonte OM;Abers MS;Aiuti A;Casari G;Lampasona V;Piemonti L;Ciceri F;Bilguvar K;Lifton RP;Vasse M;Smadja DM;Migaud M;Hadjadj J;Terrier B;Duffy D;Quintana-Murci L;van de Beek D;Roussel L;Vinh DC;Tangye SG;Haerynck F;Dalmau D;Martinez-Picado J;Brodin P;Nussenzweig MC;Boisson-Dupuis S;Rodríguez-Gallego C;Vogt G;Mogensen TH;Oler AJ;Gu J;Burbelo PD;Cohen JI;Biondi A;Bettini LR;D'Angio M;Bonfanti P;Rossignol P;Mayaux J;Rieux-Laucat F;Husebye ES;Fusco F;Ursini MV;Imberti L;Sottini A;Paghera S;Quiros-Roldan E;Rossi C;Castagnoli R;Montagna D;Licari A;Marseglia GL;Duval X;Ghosn J;HGID Lab;NIAID-USUHS Immune Response to COVID Group;COVID Clinicians;COVID-STORM Clinicians;Imagine COVID Group;French COVID Cohort Study Group;Milieu Intérieur Consortium;CoV-Contact Cohort;Amsterdam UMC Covid-19 Biobank;COVID Human Genetic Effort;Tsang JS;Goldbach-Mansky R;Kisand K;Lionakis MS;Puel A;Zhang SY;Holland SM;Gorochov G;Jouanguy E;Rice CM;Cobat A;Notarangelo LD;Abel L;Su HC;Casanova JL
通讯作者：
Casanova JL
DOI：
10.1073/pnas.2101161118
发表时间：
2021-06-15
影响因子：
11.1
作者：
Hsu JC;Laurent-Rolle M;Pawlak JB;Wilen CB;Cresswell P
通讯作者：
Cresswell P
影响因子：
5.3
作者：
Davies, Jonathan P.;Almasy, Katherine M.;Plate, Lars
通讯作者：
Plate, Lars