The emergence and global spread of SARS-CoV-2 has resulted in the urgent need for an in-depth understanding of molecular functions of viral proteins and their interactions with the host proteome. Several individual omics studies have extended our knowledge of COVID-19 pathophysiology^{1,2,3,4,5,6,7,8,9,10}. Integration of such datasets to obtain a holistic view of virus–host interactions and to define the pathogenic properties of SARS-CoV-2 is limited by the heterogeneity of the experimental systems. Here we report a concurrent multi-omics study of SARS-CoV-2 and SARS-CoV. Using state-of-the-art proteomics, we profiled the interactomes of both viruses, as well as their influence on the transcriptome, proteome, ubiquitinome and phosphoproteome of a lung-derived human cell line. Projecting these data onto the global network of cellular interactions revealed crosstalk between the perturbations taking place upon infection with SARS-CoV-2 and SARS-CoV at different levels and enabled identification of distinct and common molecular mechanisms of these closely related coronaviruses. The TGF-β pathway, known for its involvement in tissue fibrosis, was specifically dysregulated by SARS-CoV-2 ORF8 and autophagy was specifically dysregulated by SARS-CoV-2 ORF3. The extensive dataset (available at https://covinet.innatelab.org) highlights many hotspots that could be targeted by existing drugs and may be used to guide rational design of virus- and host-directed therapies, which we exemplify by identifying inhibitors of kinases and matrix metalloproteases with potent antiviral effects against SARS-CoV-2.

SARS-CoV-2 的出现和全球传播导致迫切需要深入了解病毒蛋白的分子功能及其与宿主蛋白质组的相互作用。几项个体组学研究扩展了我们对 COVID-19 病理生理学的认识^{1,2,3,4,5,6,7,8,9,10}. 整合此类数据集以全面了解病毒与宿主的相互作用并定义 SARS-CoV-2 的致病特性受到实验系统异质性的限制。在这里，我们报告了 SARS-CoV-2 和 SARS-CoV 的同时进行的多组学研究。使用最先进的蛋白质组学，我们分析了两种病毒的相互作用组，以及它们对肺源性人类细胞系的转录组、蛋白质组、泛素组和磷酸化蛋白质组的影响。将这些数据投射到全球细胞相互作用网络上，揭示了在不同水平上感染 SARS-CoV-2 和 SARS-CoV 后发生的扰动之间的串扰，并能够识别这些密切相关的冠状病毒的独特和共同的分子机制。以参与组织纤维化而闻名的 TGF-β 通路，SARS-CoV-2 ORF8 特异性失调，SARS-CoV-2 ORF3 特异性失调自噬。广泛的数据集（可在 https://covinet.innatelab.org 获得）突出显示了现有药物可能针对的许多热点，并可用于指导病毒和宿主定向疗法的合理设计，我们通过识别抑制剂来举例说明激酶和基质金属蛋白酶对 SARS-CoV-2 具有强大的抗病毒作用。