The E3 ligase TRIM22 restricts SARS-CoV-2 replication by promoting proteasomal degradation of NSP8. This study reveals that TRIM22, an interferon-stimulated gene, interacts with NSP8 and ubiquitinates it at Lys97 via K48-type ubiquitination, leading to its degradation. TRIM22 overexpression significantly reduces viral RNA and protein levels, while its knockdown enhances viral replication. NSP8, a key component of the RNA-dependent RNA polymerase complex, is found to be unstable and degraded by the proteasome. TRIM22's E3 ubiquitin ligase activity plays a crucial role in inhibiting SARS-CoV-2 replication by targeting NSP8 for degradation. The study also shows that TRIM22-mediated degradation of NSP8 is conserved across various coronaviruses, suggesting its potential as a broad-spectrum antiviral target. These findings provide new insights into the role of host factors in viral replication and highlight TRIM22 as a promising therapeutic target for developing antiviral drugs against SARS-CoV-2 and related coronaviruses. The results emphasize the importance of understanding host-virus interactions in the context of viral infections and offer a novel approach for combating viral diseases.The E3 ligase TRIM22 restricts SARS-CoV-2 replication by promoting proteasomal degradation of NSP8. This study reveals that TRIM22, an interferon-stimulated gene, interacts with NSP8 and ubiquitinates it at Lys97 via K48-type ubiquitination, leading to its degradation. TRIM22 overexpression significantly reduces viral RNA and protein levels, while its knockdown enhances viral replication. NSP8, a key component of the RNA-dependent RNA polymerase complex, is found to be unstable and degraded by the proteasome. TRIM22's E3 ubiquitin ligase activity plays a crucial role in inhibiting SARS-CoV-2 replication by targeting NSP8 for degradation. The study also shows that TRIM22-mediated degradation of NSP8 is conserved across various coronaviruses, suggesting its potential as a broad-spectrum antiviral target. These findings provide new insights into the role of host factors in viral replication and highlight TRIM22 as a promising therapeutic target for developing antiviral drugs against SARS-CoV-2 and related coronaviruses. The results emphasize the importance of understanding host-virus interactions in the context of viral infections and offer a novel approach for combating viral diseases.