SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO.
SARS-CoV-2 ORF9b inhibits RIG-I-MAVS antiviral signaling by interrupting K63-linked ubiquitination of NEMO.
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SARS-CoV-2 ORF9b 通过中断 NEMO 的 K63 泛素化来抑制 RIG-I-MAVS 抗病毒信号传导
DOI：
10.1016/j.celrep.2021.108761
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发表时间：
2021-02-16
期刊：
影响因子：
8.8
通讯作者：
Qi N
中科院分区：
文献类型：
--
作者：
Wu J;Shi Y;Pan X;Wu S;Hou R;Zhang Y;Zhong T;Tang H;Du W;Wang L;Wo J;Mu J;Qiu Y;Yang K;Zhang LK;Ye BC;Qi N
2019冠状病毒病（COVID-19）是由新型冠状病毒严重急性呼吸综合征冠状病毒2（SARS-CoV-2）引起的当前全球健康威胁。新出现的证据表明，SARS-CoV-2导致患者免疫反应失调和干扰素（IFN）表达延迟，这在很大程度上促进了COVID-19的病毒发病和发展。然而，潜在的机制仍有待阐明。在这里，我们报告了SARS-CoV-2对先天免疫反应的激活和抑制。我们发现SARS-CoV-2 RNA激活RIG-I-MAVS依赖的IFN信号通路。我们进一步发现，ORF 9 b立即积累和拮抗抗病毒I型干扰素反应期间SARS冠状病毒-2感染原代人肺泡上皮细胞。ORF 9 B靶向核因子κB（NF-κB）必需调节剂NEMO，并在病毒刺激后中断其K63连接的多聚泛素化，从而抑制经典IκB激酶α（IKKα）/β/γ-NF-κB信号传导和随后的IFN产生。因此，我们的研究结果揭示了ORF 9 b的先天免疫抑制作用，并提供了在SARS-CoV-2感染的早期阶段宿主-病毒相互作用的见解。COVID-19患者在SARS-CoV-2感染早期经历先天免疫抑制的原因尚不清楚。Wu等人报道ORF 9 b在SARS-CoV-2感染期间立即积累，并通过中断干扰素信号调节剂NEMO的K63连接的多聚泛素化来拮抗RIG-I-MAVS抗病毒I型干扰素应答。
Coronavirus disease 2019 (COVID-19) is a current global health threat caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerging evidence indicates that SARS-CoV-2 elicits a dysregulated immune response and a delayed interferon (IFN) expression in patients, which contribute largely to the viral pathogenesis and development of COVID-19. However, underlying mechanisms remain to be elucidated. Here, we report the activation and repression of the innate immune response by SARS-CoV-2. We show that SARS-CoV-2 RNA activates the RIG-I-MAVS-dependent IFN signaling pathway. We further uncover that ORF9b immediately accumulates and antagonizes the antiviral type I IFN response during SARS-CoV-2 infection on primary human pulmonary alveolar epithelial cells. ORF9b targets the nuclear factor κB (NF-κB) essential modulator NEMO and interrupts its K63-linked polyubiquitination upon viral stimulation, thereby inhibiting the canonical IκB kinase alpha (IKKα)/β/γ-NF-κB signaling and subsequent IFN production. Our findings thus unveil the innate immunosuppression by ORF9b and provide insights into the host-virus interplay during the early stage of SARS-CoV-2 infection. The reason why COVID-19 patients experience innate immunosuppression at the early stage of SARS-CoV-2 infection is unclear. Wu et al. report that ORF9b accumulates immediately during SARS-CoV-2 infection and antagonizes the RIG-I-MAVS antiviral type I interferon response by interrupting the K63-linked polyubiquitination of the interferon signaling modulator NEMO.
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DOI：
10.1126/science.abe9403
发表时间：
2020-12-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gordon DE;Hiatt J;Bouhaddou M;Rezelj VV;Ulferts S;Braberg H;Jureka AS;Obernier K;Guo JZ;Batra J;Kaake RM;Weckstein AR;Owens TW;Gupta M;Pourmal S;Titus EW;Cakir M;Soucheray M;McGregor M;Cakir Z;Jang G;O'Meara MJ;Tummino TA;Zhang Z;Foussard H;Rojc A;Zhou Y;Kuchenov D;Hüttenhain R;Xu J;Eckhardt M;Swaney DL;Fabius JM;Ummadi M;Tutuncuoglu B;Rathore U;Modak M;Haas P;Haas KM;Naing ZZC;Pulido EH;Shi Y;Barrio-Hernandez I;Memon D;Petsalaki E;Dunham A;Marrero MC;Burke D;Koh C;Vallet T;Silvas JA;Azumaya CM;Billesbølle C;Brilot AF;Campbell MG;Diallo A;Dickinson MS;Diwanji D;Herrera N;Hoppe N;Kratochvil HT;Liu Y;Merz GE;Moritz M;Nguyen HC;Nowotny C;Puchades C;Rizo AN;Schulze-Gahmen U;Smith AM;Sun M;Young ID;Zhao J;Asarnow D;Biel J;Bowen A;Braxton JR;Chen J;Chio CM;Chio US;Deshpande I;Doan L;Faust B;Flores S;Jin M;Kim K;Lam VL;Li F;Li J;Li YL;Li Y;Liu X;Lo M;Lopez KE;Melo AA;Moss FR 3rd;Nguyen P;Paulino J;Pawar KI;Peters JK;Pospiech TH Jr;Safari M;Sangwan S;Schaefer K;Thomas PV;Thwin AC;Trenker R;Tse E;Tsui TKM;Wang F;Whitis N;Yu Z;Zhang K;Zhang Y;Zhou F;Saltzberg D;QCRG Structural Biology Consortium;Hodder AJ;Shun-Shion AS;Williams DM;White KM;Rosales R;Kehrer T;Miorin L;Moreno E;Patel AH;Rihn S;Khalid MM;Vallejo-Gracia A;Fozouni P;Simoneau CR;Roth TL;Wu D;Karim MA;Ghoussaini M;Dunham I;Berardi F;Weigang S;Chazal M;Park J;Logue J;McGrath M;Weston S;Haupt R;Hastie CJ;Elliott M;Brown F;Burness KA;Reid E;Dorward M;Johnson C;Wilkinson SG;Geyer A;Giesel DM;Baillie C;Raggett S;Leech H;Toth R;Goodman N;Keough KC;Lind AL;Zoonomia Consortium;Klesh RJ;Hemphill KR;Carlson-Stevermer J;Oki J;Holden K;Maures T;Pollard KS;Sali A;Agard DA;Cheng Y;Fraser JS;Frost A;Jura N;Kortemme T;Manglik A;Southworth DR;Stroud RM;Alessi DR;Davies P;Frieman MB;Ideker T;Abate C;Jouvenet N;Kochs G;Shoichet B;Ott M;Palmarini M;Shokat KM;García-Sastre A;Rassen JA;Grosse R;Rosenberg OS;Verba KA;Basler CF;Vignuzzi M;Peden AA;Beltrao P;Krogan NJ
通讯作者：
Krogan NJ
影响因子：
168.9
作者：
Huang, Chaolin;Wang, Yeming;Cao, Bin
通讯作者：
Cao, Bin
影响因子：
11.8
作者：
Qin, Chuan;Zhou, Luoqi;Tian, Dai-Shi
通讯作者：
Tian, Dai-Shi
影响因子：
5.4
作者：
Kopecky-Bromberg, Sarah A.;Martinez-Sobrido, Luis;Palese, Peter
通讯作者：
Palese, Peter
影响因子：
56.9
作者：
Gentili, Matteo;Kowal, Joanna;Manel, Nicolas
通讯作者：
Manel, Nicolas