Abstract
Viral proteins localize within subcellular compartments to subvert host machinery and promote pathogenesis. To study SARS-CoV-2 biology, we generated an atlas of 2422 human proteins vicinal to 17 SARS-CoV-2 viral proteins using proximity proteomics. This identified viral proteins at specific intracellular locations, such as association of accessary proteins with intracellular membranes, and projected SARS-CoV-2 impacts on innate immune signaling, ER-Golgi transport, and protein translation. It identified viral protein adjacency to specific host proteins whose regulatory variants are linked to COVID-19 severity, including the TRIM4 interferon signaling regulator which was found proximal to the SARS-CoV-2 M protein. Viral NSP1 protein adjacency to the EIF3 complex was associated with inhibited host protein translation whereas ORF6 localization with MAVS was associated with inhibited RIG-I 2CARD-mediated IFNB1 promoter activation. Quantitative proteomics identified candidate host targets for the NSP5 protease, with specific functional cleavage sequences in host proteins CWC22 and FANCD2. This data resource identifies host factors proximal to viral proteins in living human cells and nominates pathogenic mechanisms employed by SARS-CoV-2.
Highlights
Coronaviruses comprise a diverse family of large positive-sense single stranded (+ss)RNA enveloped viruses that cause respiratory and gastrointestinal disease
We create a database of proximal host proteins to 17 SARS-CoV-2 viral proteins
We validate that NSP1 is proximal to the EIF3 translation initiation complex and is a potent inhibitor of translation
Summary
Coronaviruses comprise a diverse family of large positive-sense single stranded (+ss)RNA enveloped viruses that cause respiratory and gastrointestinal disease. In addition to common seasonal coronaviruses, a number of strains can cause severe disease, as seen in the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) virus outbreak in 2003 [1], the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) virus outbreak in 2012 [2] and the 2019 outbreak of SARS-CoV-2 [3]. This viral family has large (26 to 32kb) genomes that encode tens of viral proteins. The function of many SARS-CoV-2 accessory proteins is either unknown or highly variable across differing coronaviruses, underscoring the need to begin mapping their putative localizations and functions
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