The proximal proteome of 17 SARS-CoV-2 proteins links to disrupted antiviral signaling and host translation

Abstract

Viral proteins localize within subcellular compartments to subvert host machinery and 25 promote pathogenesis. To study SARS-CoV-2 biology, we generated an atlas of 2422 26 human proteins vicinal to 17 SARS-CoV-2 viral proteins using proximity proteomics. This 27 identified viral proteins at specific intracellular locations, such as association of accessary 28 proteins with intracellular membranes, and projected SARS-CoV-2 impacts on innate 29 immune signaling, ER-Golgi transport, and protein translation. It identified viral protein 30 adjacency to specific host proteins whose regulatory variants are linked to COVID-19 31 severity, including the TRIM4 interferon signaling regulator which was found proximal to 32 the SARS-CoV-2 M protein. Viral NSP1 protein adjacency to the EIF3 complex was 33 associated with inhibited host protein translation whereas ORF6 localization with MAVS 34 was associated with inhibited RIG-I 2CARD-mediated IFNB1 promoter activation. 35 Quantitative proteomics identified candidate host targets for the NSP5 protease, with 36 specific functional cleavage sequences in host proteins CWC22 and FANCD2. This data 37 resource identifies host factors proximal to viral proteins in living human cells and 38 nominates pathogenic mechanisms employed by SARS-CoV-2.

SARS-CoV-2 Nsp14 activates NF-κB signaling and induces IL-8 upregulation

“…Nsp14 may manipulate IMPDH2 to increase the phosphorylation of IKKβ and IκBα to promote nuclear translocation and phosphorylation of p65 (24). In addition, we also noticed that Nsp14 partially localizes in the nuclei of cells (Fig 1C, D), similar to findings from other groups (51,52). Thus, Nsp14 may associate with and modify the host cellular RNAs via its exonuclease and methyltransferase activities.…”

Genetic overlap between idiopathic pulmonary fibrosis and COVID-19

“…The rs2897075_T allele at 7q22.1, associated with increased IPF and COVID-19 risk, was linked to decreased TRIM4 and ZKSCAN1 expression. TRIM4 is an important regulator of virus-induced interferon induction pathways and a proteomic study identified significant adjacency between SARS-CoV-2 M protein and TRIM4 [13]. Viral infection-induced micro-injury to the alveolar epithelium is thought to be a trigger for development of IPF [14], suggesting the interferon-mediated innate immune response could be central to both risk of chronic lung disease and worse outcomes due to SARS-CoV-2 infection.…”

Genetic overlap between idiopathic pulmonary fibrosis and COVID−19

“…The rs2897075_T allele at 7q22.1, associated with increased IPF and COVID-19 risk, was linked to decreased TRIM4 and ZKSCAN1 expression. TRIM4 is an important regulator of virus-induced interferon induction pathways and a proteomic study identified significant adjacency between SARS-CoV-2 M protein and TRIM4 11 . Viral infection-induced micro-injury to the alveolar epithelium is thought to be a trigger for development of IPF 12 , suggesting the interferon-mediated innate immune response could be central to both risk of chronic lung disease and worse outcomes due to SARS-CoV-2 infection.…”