Interaction of HDAC2 with SARS-CoV-2 NSP5 and IRF3 Is Not Required for NSP5-Mediated Inhibition of Type I Interferon Signaling Pathway.
Interaction of HDAC2 with SARS-CoV-2 NSP5 and IRF3 Is Not Required for NSP5-Mediated Inhibition of Type I Interferon Signaling Pathway.
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DOI：
10.1128/spectrum.02322-22
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发表时间：
2022-10-26
影响因子：
3.7
通讯作者：
Toth, Zsolt
中科院分区：
文献类型：
--
作者：
Naik, Nenavath Gopal;Lee, See-Chi;Veronese, Beatriz H. S.;Ma, Zhe;Toth, Zsolt
在过去的两年中，已经发表了几项关于SARS-CoV-2蛋白的全球病毒-宿主相互作用组研究，目的是更好地了解特定病毒蛋白如何破坏或利用不同的细胞过程来促进病毒感染和发病。然而，大多数病毒-宿主蛋白质相互作用尚未得到实验证实，其生物学意义在很大程度上是未知的。本研究的目的是验证NSP 5（SARS-CoV-2的主要蛋白酶）与宿主表观遗传因子组蛋白脱乙酰酶2（HDAC 2）的相互作用，并测试HDAC 2是否是NSP 5介导的I型干扰素信号通路抑制所必需的。我们的研究结果表明，NSP 5可以显着降低免疫应答基因的子集，如IL-6，IL-1β和IFNβ的表达，这需要NSP 5的蛋白酶活性。我们还发现NSP 5可以抑制仙台病毒、RNA传感器和DNA传感器介导的IFNβ启动子的诱导，阻断IFN应答途径，并减少IFN刺激基因的表达。我们还提供了HDAC 2与IRF 3相互作用的证据，NSP 5可以通过结合IRF 3和HDAC 2来消除它们的相互作用。另外，我们发现HDAC 2在IFNβ和IFN诱导的启动子的调节中起抑制作用，但我们的结果表明HDAC 2不参与NSP 5介导的IFNβ基因表达的抑制。综上所述，我们的数据表明，NSP 5与HDAC 2相互作用，但NSP 5以HDAC 2非依赖性方式抑制IFNβ基因表达和干扰素信号通路。SARS-CoV-2已经开发了多种策略来拮抗宿主的抗病毒反应，例如阻断IFN信号通路，这有利于病毒的复制和传播。最近的SARS-CoV-2蛋白相互作用图谱显示，主要的病毒蛋白酶NSP 5与宿主表观遗传因子HDAC 2相互作用，但这种相互作用尚未得到实验证实，其生物学意义仍不清楚。在这里，我们不仅验证了HDAC 2与NSP 5的相互作用，而且我们还发现HDAC 2也与IRF 3结合，并且NSP 5可以破坏IRF 3-HDAC 2复合物。此外，我们的研究结果表明，无论是病毒感染、RNA还是DNA传感器激活了IFN信号通路，NSP 5都能有效地抑制IFN信号通路，但我们的数据表明，HDAC 2不参与NSP 5介导的IFNβ启动子诱导和IFNβ基因表达的抑制。
Over the last 2 years, several global virus-host interactome studies have been published with SARS-CoV-2 proteins with the purpose of better understanding how specific viral proteins can subvert or utilize different cellular processes to promote viral infection and pathogenesis. However, most of the virus–host protein interactions have not yet been confirmed experimentally, and their biological significance is largely unknown. The goal of this study was to verify the interaction of NSP5, the main protease of SARS-CoV-2, with the host epigenetic factor histone deacetylase 2 (HDAC2) and test if HDAC2 is required for NSP5-mediated inhibition of the type I interferon signaling pathway. Our results show that NSP5 can significantly reduce the expression of a subset of immune response genes such as IL-6, IL-1β, and IFNβ, which requires NSP5’s protease activity. We also found that NSP5 can inhibit Sendai virus-, RNA sensor-, and DNA sensor-mediated induction of IFNβ promoter, block the IFN response pathway, and reduce the expression of IFN-stimulated genes. We also provide evidence for HDAC2 interacting with IRF3, and NSP5 can abrogate their interaction by binding to both IRF3 and HDAC2. In addition, we found that HDAC2 plays an inhibitory role in the regulation of IFNβ and IFN-induced promoters, but our results indicate that HDAC2 is not involved in NSP5-mediated inhibition of IFNβ gene expression. Taken together, our data show that NSP5 interacts with HDAC2 but NSP5 inhibits the IFNβ gene expression and interferon-signaling pathway in an HDAC2-independent manner. IMPORTANCE SARS-CoV-2 has developed multiple strategies to antagonize the host antiviral response, such as blocking the IFN signaling pathway, which favors the replication and spreading of the virus. A recent SARS-CoV-2 protein interaction mapping revealed that the main viral protease NSP5 interacts with the host epigenetic factor HDAC2, but the interaction was not confirmed experimentally and its biological importance remains unclear. Here, we not only verified the interaction of HDAC2 with NSP5, but we also found that HDAC2 also binds to IRF3, and NSP5 can disrupt the IRF3-HDAC2 complex. Furthermore, our results show that NSP5 can efficiently repress the IFN signaling pathway regardless of whether viral infections, RNA, or DNA sensors activated it. However, our data indicate that HDAC2 is not involved in NSP5-mediated inhibition of IFNβ promoter induction and IFNβ gene expression.
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影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
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：
28.3
作者：
Gorbalenya, Alexander E.;Baker, Susan C.;Ziebuhr, John
通讯作者：
Ziebuhr, John
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影响因子：
15.3
作者：
Huai, Wanwan;Liu, Xingguang;Cao, Xuetao
通讯作者：
Cao, Xuetao
影响因子：
9.2
作者：
Fung SY;Siu KL;Lin H;Yeung ML;Jin DY
通讯作者：
Jin DY