Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.
Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms.
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DOI：
10.1126/science.abe9403
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发表时间：
2020-12-04
期刊：
影响因子：
--
通讯作者：
Krogan NJ
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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
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）与致命的冠状病毒SARS-CoV-1和中东呼吸综合征冠状病毒（MERS-CoV）密切相关。相当大的努力集中在开发治疗方法上，而跨冠状病毒的治疗方法将特别有价值。为了揭示被病毒劫持的宿主因素，戈登等人绘制了SARS-CoV-2、SARS-CoV-1和MERS-CoV的病毒和人类蛋白之间的相互作用;分析了病毒蛋白在人类细胞中的定位;并使用基因筛选来识别增强或抑制病毒感染的宿主因素。对于病毒生命周期所必需的相互作用的子集，作者确定了冷冻电子显微镜结构并挖掘了患者数据，以了解靶向宿主因素如何与临床结局相关。eabe 9403比较三种致命冠状病毒的宿主相互作用，确定了常见的劫持途径和潜在的药物靶点。在不到20年的时间里出现了三种致命的冠状病毒，加上COVID-19大流行的紧迫性，促使人们努力开发新的治疗策略，包括重新利用现有的药物。在对三种致病性人类冠状病毒严重急性呼吸综合征冠状病毒1（SARS-CoV-1），SARS-CoV-2和中东呼吸综合征冠状病毒（MERS-CoV）进行比较分析后，我们确定了共同的生物学和宿主导向的药物靶标，以优先考虑有可能快速部署的治疗方法，以应对当前和未来的冠状病毒爆发。扩展我们最近的SARS-CoV-2相互作用组，我们绘制了SARS-CoV-1和MERS-CoV的病毒-宿主蛋白-蛋白相互作用，并评估了三种毒株中每种病毒蛋白的细胞定位。我们对SARS-CoV-2相互作用因子进行了两次遗传筛选，以优先考虑功能相关的宿主因子，并在结构上表征了一种病毒-宿主相互作用。然后，我们通过评估遗传队列中的风险或观察现实世界证据中宿主因子靶向药物的有效性，测试了另外三种宿主因子的临床相关性。对SARS-CoV-2的389个相互作用物、SARS-CoV-1的366个相互作用物和MERS-CoV的296个相互作用物的定量比较突出了与宿主过程的相互作用，这些过程在所有三种病毒中都是保守的，包括来自不同病毒株的非正构蛋白似乎扮演着类似的角色。我们还通过显微镜定位了每个单独表达的病毒蛋白，然后针对14种SARS-CoV-2蛋白提出并验证了抗血清，以确定它们在感染过程中的定位。在两个独立的遗传干扰筛选的基础上，我们确定了73个宿主因子，当耗尽时，引起SARS-CoV-2复制的显着变化。从这个潜在的药物靶点列表中，我们验证了Tom 70、IL 17 RA、PGES-2和SigmaR 1的生物学和临床相关性。Tom 70是一种线粒体输入受体，与SARS-CoV-2 ORF 9 b复合，其3-kDa冷冻电子显微镜结构提供了对ORF 9 b如何调节宿主免疫反应的深入了解。使用策划的全基因组关联研究数据，我们发现具有血浆中可溶性IL 17 RA水平较高的基因型的个体COVID-19住院治疗的风险降低。为了证明我们的数据对药物再利用的价值，我们确定了SARS-CoV-2患者，他们被处方了针对优先目标的药物，并询问他们与使用不抑制SARS-CoV-2的临床相似药物治疗的精心匹配的患者相比，他们的表现如何。与塞来昔布和非典型抗精神病药物相比，吲哚美辛（一种宿主因子PGES-2的抑制剂）和典型抗精神病药物（因其与σ受体的相互作用而被选择）分别显示出对COVID-19的有效性。通过采用综合和协作的方法，我们确定了三种致病性冠状病毒株的保守机制，并进一步研究了潜在的药物靶点。这种通用的方法广泛适用于其他传染病和疾病领域。（左）病毒-人类蛋白质-蛋白质相互作用网络图谱、病毒蛋白质定位研究和功能遗传筛选为了解每种病毒的共同特征和个体特征提供了关键见解。（右）临床数据集中的结构研究和假设检验证明了这种方法在优先考虑治疗策略方面的实用性。Nsp，非结构蛋白; ORF，开放阅读框; ER，内质网。由严重急性呼吸系统综合征冠状病毒2型（SARS-CoV-2）引起的COVID-19大流行对公共卫生和全球经济构成严重威胁。SARS-CoV-2与致命性更高但传播性更低的冠状病毒SARS-CoV-1和中东呼吸综合征冠状病毒（MERS-CoV）密切相关。在这里，我们进行了比较病毒-人蛋白质-蛋白质相互作用和病毒蛋白定位分析所有三种病毒。随后的功能性遗传筛选确定了在功能上影响冠状病毒增殖的宿主因子，包括Tom 70，一种与SARS-CoV-1和SARS-CoV-2 ORF 9 b相互作用的线粒体伴侣蛋白，我们使用冷冻电子显微镜在结构上表征了这种相互作用。将基因验证的宿主因素与COVID-19患者基因数据和医疗账单记录相结合，确定了值得进一步分子和临床研究的分子机制和潜在药物治疗。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is closely related to the deadly coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Considerable efforts are focused on developing treatments, and therapies that work across coronaviruses would be particularly valuable. Shedding light on the host factors hijacked by the viruses, Gordon et al. mapped the interactions between viral and human proteins for SARS-CoV-2, SARS-CoV-1, and MERS-CoV; analyzed the localization of viral proteins in human cells; and used genetic screening to identify host factors that either enhance or inhibit viral infection. For a subset of the interactions essential for the virus life cycle, the authors determined the cryo–electron microscopy structures and mined patient data to understand how targeting host factors may be relevant to clinical outcomes. Science, this issue p. eabe9403 Comparison of host interactions of three lethal coronaviruses identifies commonly hijacked pathways and potential drug targets. The emergence of three lethal coronaviruses in <20 years and the urgency of the COVID-19 pandemic have prompted efforts to develop new therapeutic strategies, including by repurposing existing agents. After performing a comparative analysis of the three pathogenic human coronaviruses severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV), we identified shared biology and host-directed drug targets to prioritize therapeutics with potential for rapid deployment against current and future coronavirus outbreaks. Expanding on our recent SARS-CoV-2 interactome, we mapped the virus-host protein-protein interactions for SARS-CoV-1 and MERS-CoV and assessed the cellular localization of each viral protein across the three strains. We conducted two genetic screens of SARS-CoV-2 interactors to prioritize functionally-relevant host factors and structurally characterized one virus-host interaction. We then tested the clinical relevance of three more host factors by assessing risk in genetic cohorts or observing effectiveness of host factor–targeting drugs in real-world evidence. Quantitative comparison of the 389 interactors of SARS-CoV-2, 366 of SARS-CoV-1, and 296 of MERS-CoV highlighted interactions with host processes that are conserved across all three viruses, including where nonorthologous proteins from different virus strains seem to fill similar roles. We also localized each individually-expressed viral protein by microscopy and then raised and validated antisera against 14 SARS-CoV-2 proteins to determine their localization during infection. On the basis of two independent genetic perturbation screens, we identified 73 host factors that, when depleted, caused significant changes in SARS-CoV-2 replication. From this list of potential drug targets, we validated the biological and clinical relevance of Tom70, IL17RA, PGES-2, and SigmaR1. A 3-Å cryo–electron microscopy structure of Tom70, a mitochondrial import receptor, in complex with SARS-CoV-2 ORF9b, provides insight into how ORF9b may modulate the host immune response. Using curated genome-wide association study data, we found that individuals with genotypes corresponding to higher soluble IL17RA levels in plasma are at decreased risk of COVID-19 hospitalization. To demonstrate the value of our data for drug repurposing, we identified SARS-CoV-2 patients who were prescribed drugs against prioritized targets and asked how they fared compared with carefully matched patients treated with clinically similar drugs that do not inhibit SARS-CoV-2. Both indomethacin, an inhibitor of host factor PGES-2, and typical antipsychotics, selected for their interaction with sigma receptors, showed effectiveness against COVID-19 compared with celecoxib and atypical antipsychotics, respectively. By employing an integrative and collaborative approach, we identified conserved mechanisms across three pathogenic coronavirus strains and further investigated potential drug targets. This versatile approach is broadly applicable to other infectious agents and disease areas. (Left) Viral-human protein-protein interaction network mapping, viral protein localization studies, and functional genetic screens provide key insights into the shared and individual characteristics of each virus. (Right) Structural studies and hypothesis testing in clinical datasets demonstrate the utility of this approach for prioritizing therapeutic strategies. Nsp, nonstructural protein; ORF, open reading frame; ER, endoplasmic reticulum. The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a grave threat to public health and the global economy. SARS-CoV-2 is closely related to the more lethal but less transmissible coronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV). Here, we have carried out comparative viral-human protein-protein interaction and viral protein localization analyses for all three viruses. Subsequent functional genetic screening identified host factors that functionally impinge on coronavirus proliferation, including Tom70, a mitochondrial chaperone protein that interacts with both SARS-CoV-1 and SARS-CoV-2 ORF9b, an interaction we structurally characterized using cryo–electron microscopy. Combining genetically validated host factors with both COVID-19 patient genetic data and medical billing records identified molecular mechanisms and potential drug treatments that merit further molecular and clinical study.
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DOI：
10.1107/s2059798318009324
发表时间：
2018-09-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Klaholz BP;Moriarty NW;Poon BK;Sobolev OV;Terwilliger TC;Adams PD;Urzhumtsev A
通讯作者：
Urzhumtsev A
DOI：
10.1083/jcb.201708044
发表时间：
2018-04-02
期刊：
The Journal of cell biology
影响因子：
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作者：
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通讯作者：
Herrmann JM
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.8
作者：
Durairaj, Janani;Akdel, Mehmet;van Dijk, Aalt D. J.
通讯作者：
van Dijk, Aalt D. J.
DOI：
10.1016/j.csbj.2020.03.011
发表时间：
2020-01-01
影响因子：
6
作者：
Akdel, Mehmet;Durairaj, Janani;van Dijk, Aalt D. J.
通讯作者：
van Dijk, Aalt D. J.