An antibody-based proximity labeling map reveals mechanisms of SARS-CoV-2 inhibition of antiviral immunity

Zhang, Yuehui; Shang, Limin; Zhang, Jing; Liu, Yuchen; Jin, Chaozhi; Zhao, Yanan; Lei, Xiaobo; Wang, Wenjing; Xiao, Xia; Zhang, Xiuyuan; Liu, Yujiao; Liu, Linlin; Zhuang, Meng-Wei; Mi, Qingkun; Tian, Chunyan; Wang, Jianwei; He, Fuchu; Wang, Pei-Hui; Wang, Jian

The global epidemic caused by the coronavirus severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in the infection of over 200 million people. To extend the knowledge of interactions between SARS-CoV-2 and humans, we systematically investigate the interactome of 29 viral proteins in human cells by using an antibody-based TurboID assay. In total, 1,388 high-confidence human proximal proteins with biotinylated sites are identified. Notably, we find that SARS-CoV-2 manipulates the antiviral and immune responses. We validate that the membrane protein ITGB1 associates angiotensin-converting enzyme 2 (ACE2) to mediate SARS-CoV-2 entry. Moreover, we reveal that SARS-CoV-2 proteins inhibit activation of the interferon pathway through the mitochondrial protein mitochondrial antiviral-signaling protein (MAVS) and the methyltransferase SET domain containing 2, histone lysine methyltransferase (SETD2). We propose 111 potential drugs for the clinical treatment of coronavirus disease 2019 (COVID-19) and identify three compounds that significantly inhibit the replication of SARS-CoV-2. The proximity labeling map of SARS-CoV-2 and humans provides a resource for elucidating the mechanisms of viral infection and developing drugs for COVID-19 treatment.