Ubiquitin-Modified Proteome of SARS-CoV-2-Infected Host Cells Reveals Insights into Virus–Host Interaction and Pathogenesis

Abstract

The outbreak of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has posed a serious threat to global public health. The mechanism of pathogenesis and the host immune response to SARS-CoV-2 infection are largely unknown. In the present study, we applied a quantitative proteomic technology to identify and quantify the ubiquitination changes that occur in both the virus and the Vero E6 cells during SARS-CoV-2 infection. By applying label-free, quantitative liquid chromatography with tandem mass spectrometry proteomics, 8943 lysine ubiquitination sites on 3086 proteins were identified, of which 138 sites on 104 proteins were quantified as significantly upregulated, while 828 sites on 447 proteins were downregulated at 72 h post-infection. Bioinformatics analysis suggested that SARS-CoV-2 infection might modulate host immune responses through the ubiquitination of important proteins, including USP5, IQGAP1, TRIM28, and Hsp90. Ubiquitination modification was also observed on 11 SAR-CoV-2 proteins, including proteins involved in virus replication and inhibition of the host innate immune response. Our study provides new insights into the interaction between SARS-CoV-2 and the host as well as potential targets for the prevention and treatment of COVID-19.

COVID-19 in Children: Expressions of Type I/II/III Interferons, TRIM28, SETDB1, and Endogenous Retroviruses in Mild and Severe Cases

“…TRIM28 recruits SETDB1 for SUMOylation, a crucial transient post-translational event involved in essential cell functions such as transcriptional repression, RNA splicing, and protein degradation [ 77 , 78 ]. Ubiquitination changes in viral proteins and in host proteins were observed in SARS-CoV-2-infected cells [ 79 ]. Interestingly, the ubiquitination of the ACE2 receptor by E3 ligases leads to its degradation [ 80 , 81 ].…”

Know your enemy and know yourself – the case of SARS-CoV-2 host factors

“…The S protein is ubiquitylated by HECT-E3 ubiquitin ligases, e.g. , NEDD4 and WWP1, and chemical inhibitions of these E3 ubiquitin ligases can potently decrease SARS-CoV-2 infection and egress [ 75 , 76 ]. The ORF7a protein requires polyubiquitylation to confer the ability to antagonize host innate immunity by blocking STAT2 phosphorylation [ 77 ].…”

CRISPR screens for host factors critical for infection by SARS-CoV-2 variants of concern identify GATA6 as a central modulator of ACE2

“…While ubiquitination of viral proteins can be used by the host as a defense mechanism by destroying the incoming pathogen, viruses have adapted to exploit this cellular process to enhance various steps of the replication cycle and increase pathogenesis [46]. Indeed, in addition to highly modified ubiquitin-proteome of SARS-CoV-2-Infected host cells, ubiquitination modifications were observed also on SARS-CoV-2 proteins, and these modifications were reported to inhibit the host innate immune response [46][47][48]. IRF6 gene is a transcriptional activator with well-established role in the development of the epidermis.…”