A virus caught using the cell’s own tagging system

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COVID-19 is caused by SARS-CoV-2, a virus responsible for millions of confirmed deaths worldwide. Like many viruses, SARS-CoV-2 hijacks the host’s post-translational modification systems to enhance viral replication and evade innate immune responses. This article focuses on one such system: ubiquitination. Ubiquitination is a process in which a small regulatory protein called ubiquitin is covalently attached to a target protein, determining that protein’s fate and activity. The process requires a cascade of enzymes, ending with an E3 ligase, which selects the target and carries out the final tagging step. Several SARS-CoV-2 proteins are ubiquitinated. This study, led by researchers at Yale School of Medicine in collaboration with Rutgers New Jersey Medical School, focused on NSP12, the RNA-dependent RNA polymerase that copies the viral genome.

Figure. Viral titers drop when host enzymes are knocked down. A549-AT cells treated with siRNA against MYCBP2, UBE2D3, or both were infected with SARS-CoV-2 (MOI 0.1, 48 h). Reducing MYCBP2 lowered titers roughly 10-fold compared with the scrambled control. Figure from Boytz et al., mSphere 2026 (CC BY 4.0). — **Figure.** Viral titers drop when host enzymes are knocked down. A549-AT cells treated with siRNA against MYCBP2, UBE2D3, or both were infected with SARS-CoV-2 (MOI 0.1, 48 h). Reducing MYCBP2 lowered titers roughly 10-fold compared with the scrambled control. Figure from Boytz et al., mSphere 2026 (CC BY 4.0).

An interesting finding in this study is that NSP12 ubiquitination occurred at a serine residue rather than a lysine, the amino acid where ubiquitin is normally attached. The modification was carried out by MYCBP2, an atypical host E3 ligase capable of transferring ubiquitin to serine and threonine. To the authors’ knowledge, this is the first report of serine ubiquitination on a viral protein. These findings were established using immunoprecipitation, mass spectrometry, and site-directed mutagenesis in transfected cells. This is notable because earlier studies, carried out under destabilizing conditions such as heat or arsenic trioxide treatment, found that NSP12 ubiquitination promoted its degradation and reduced viral titers. Here, during infection without such stimuli, NSP12 was instead stable against proteasomal degradation, and reducing MYCBP2 lowered viral titers in plaque assays, suggesting this modification may support rather than restrict viral replication. The authors note that several questions remain open. What S564 ubiquitination does to the polymerase is still undefined, whether it alters RNA binding, enzymatic activity, protein shape, or how the replication complex assembles are all things future work will need to test directly. They also raise the possibility that the differences in ubiquitination they observed between coronaviruses, and between SARS-CoV-2 variants, could underlie differences in how these viruses behave. Whether that translates into real effects on fitness, replication kinetics, or disease severity remains to be determined.

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READ MORE: Boytz R, Layne J, Skerrit-Genelus C, Ye C, Hsu JC-C, Martinez-Sobrido L, Laurent-Rolle M. Serine ubiquitination of the SARS-CoV-2 RdRp by the non-canonical E3 ligase MYCBP2. mSphere. 2026 Sep 29;11(9):e0037326. doi: 10.1128/msphere.00373-26. Epub 2026 Sep 1. PMID: 42678169; PMCID: PMC13621839.