The study investigates the role of tripartite motif-containing 22 (TRIM22) in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It finds that TRIM22 acts as an E3 ubiquitin ligase, promoting the proteasomal degradation of non-structural protein 8 (NSP8), a key component of the RNA-dependent RNA polymerase (RdRp) complex. The degradation of NSP8 is mediated by TRIM22 via K48-type ubiquitination at Lys97. Overexpression of TRIM22 significantly reduces viral RNA and protein levels, while its knockdown enhances viral replication. The study also shows that interferon (IFN) signaling pathway activation upon viral infection increases TRIM22 expression, suggesting a potential therapeutic strategy for treating SARS-CoV-2 infection using IFNs. Additionally, the conserved nature of NSP8 across different SARS-CoV-2 strains and other coronaviruses indicates that TRIM22-mediated degradation may be a broad-spectrum antiviral mechanism. These findings provide new insights into the antiviral mechanisms against SARS-CoV-2 and suggest potential targets for drug development.The study investigates the role of tripartite motif-containing 22 (TRIM22) in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It finds that TRIM22 acts as an E3 ubiquitin ligase, promoting the proteasomal degradation of non-structural protein 8 (NSP8), a key component of the RNA-dependent RNA polymerase (RdRp) complex. The degradation of NSP8 is mediated by TRIM22 via K48-type ubiquitination at Lys97. Overexpression of TRIM22 significantly reduces viral RNA and protein levels, while its knockdown enhances viral replication. The study also shows that interferon (IFN) signaling pathway activation upon viral infection increases TRIM22 expression, suggesting a potential therapeutic strategy for treating SARS-CoV-2 infection using IFNs. Additionally, the conserved nature of NSP8 across different SARS-CoV-2 strains and other coronaviruses indicates that TRIM22-mediated degradation may be a broad-spectrum antiviral mechanism. These findings provide new insights into the antiviral mechanisms against SARS-CoV-2 and suggest potential targets for drug development.