Multiomics approach reveals the ubiquitination-specific processes hijacked by SARS-CoV-2

Abstract

The Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a global pandemic that seriously threatens health and socioeconomic development, but the existed antiviral drugs and vaccines still cannot yet halt the spread of the epidemic. Therefore, a comprehensive and profound understanding of the pathogenesis of SARS-CoV-2 is urgently needed to explore effective therapeutic targets. Here, we conducted a multiomics study of SARS-CoV-2-infected lung epithelial cells, including transcriptomic, proteomic, and ubiquitinomic. Multiomics analysis showed that SARS-CoV-2-infected lung epithelial cells activated strong innate immune response, including interferon and inflammatory responses. Ubiquitinomic further reveals the underlying mechanism of SARS-CoV-2 disrupting the host innate immune response. In addition, SARS-CoV-2 proteins were found to be ubiquitinated during infection despite the fact that SARS-CoV-2 itself didn’t code any E3 ligase, and that ubiquitination at three sites on the Spike protein could significantly enhance viral infection. Further screening of the E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) library revealed four E3 ligases influencing SARS-CoV-2 infection, thus providing several new antiviral targets. This multiomics combined with high-throughput screening study reveals that SARS-CoV-2 not only modulates innate immunity, but also promotes viral infection, by hijacking ubiquitination-specific processes, highlighting potential antiviral and anti-inflammation targets.

Ubiquitin Ligase Parkin Regulates the Stability of SARS-CoV-2 Main Protease and Suppresses Viral Replication

“…Ubiquitination of Orf7a of SARS-CoV-2 inhibits IFN signaling and reduces ER stress and apoptosis of the infected cell to promote viral replication. , Overall, UPS may play a multifaceted role in the viral-host interaction during SARS-CoV-2 infection. A comprehensive survey of the UPS system has identified numerous E3 UB ligases or deubiquitinating enzymes (DUBs) that can either enhance or suppress the replication of SARS-CoV-2 . It would be interesting to further characterize the role of Parkin in collaborating with or acting against other E3s to defend the host cells from viral infection.…”

Genome-scale CRISPR‒Cas9 screen identifies novel host factors as potential therapeutic targets for SARS-CoV-2 infection

“…2). Several SARS-CoV-2 proteins that are ubiquitinated have been reported (41)(42)(43)(44)(45), but further analysis is needed to determine whether TRIM28 and TRIM33 are involved in the ubiquitination of viral proteins. EHMT1/2 catalyses the methylation of histones and nonhistone proteins, and the substrates of the enzymes that contribute to SARS-CoV-2 replication may be either host or viral proteins or both.…”

“…2). Several SARS-CoV-2 proteins that are ubiquitinated have been reported (41–45), but further analysis is needed to determine whether TRIM28 and TRIM33 are involved in the ubiquitination of viral proteins.…”

Combined Proteomic and Phosphoproteomic Characterization of the Molecular Regulators and Functional Modules During Pancreatic Progenitor Cell Development

“…Following previously reported protocols, 15 tryptic peptides were dissolved in solvent A (0.1% formic acid, 2% acetonitrile/in water), and then immediately loaded onto a ReproSil-Pur Basic C18 column (1.9 μm, 100 μm × 25 cm, 120 Å ReproSilPurC18 resins, GmbH, Germany). A nanoElute high-performance liquid chromatography-MS system (Bruker Daltonics) was used at a constant flow rate of 450 nL/min, and peptides were separated with a gradient of solvent B (0.1% formic acid in acetonitrile) at 6−24% over 70 min, 24−35% in 14 min, increasing to 80% in 3 min, and then holding at 80% for the final 3 min.…”