ArticleJournal of virology2026
Cleavage of TOM1 by the SARS-CoV-2 main protease NSP5 prevents autophagic degradation of viral envelope.
Article in Journal of virology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Autophagy plays a critical role in viral replication and the regulation of host immune responses. Although the TOM1-TOLLIP complex has been implicated in immune signaling, cargo trafficking, and endocytosis, its role in viral replication has not been defined. Here, we demonstrate that the SARS-CoV-2 main protease (NSP5) cleaves TOM1 at residue Q354 through its protease activity. This cleavage is also observed with the main proteases of SARS-CoV and MERS-CoV. Importantly, TOM1 overexpression suppresses SARS-CoV-2 replication in HEK293T-hACE2 and Vero cells, while TOM1 knockout via CRISPR-Cas9 significantly enhances viral propagation, indicating that TOM1 functions as a novel restriction factor against SARS-CoV-2 infection. Moreover, various TOM1 orthologs from diverse species, including cattle, bats, monkeys, mice, and ducks, show similar restriction to SARS-CoV-2, but they all are antagonized by NSP5 cleavage. Mechanistically, we found that TOM1 recruits the autophagy receptor TOLLIP to target SARS-CoV-2 envelope (E) protein for autophagic degradation, thereby limiting viral replication. These findings highlight the importance of the TOM1-TOLLIP complex in host defense and discover that SARS-CoV-2 exploits a conserved NSP5-mediated TOM1 cleavage mechanism to evade host antiviral defenses.IMPORTANCEViruses must overcome the body's natural defenses in order to replicate and spread. One important cellular defense mechanism is autophagy, a process that helps cells remove harmful proteins and pathogens. In this study, we discovered that a host protein called TOM1 acts as a restriction factor that helps limit the replication of SARS-CoV-2, the virus responsible for COVID-19. TOM1 works together with another protein, TOLLIP, to direct envelope proteins to the cell's degradation system, thereby reducing viral replication. However, SARS-CoV-2 has evolved a strategy to counter this defense. The viral main protease (NSP5) cleaves TOM1, disabling its antiviral activity. This mechanism is conserved among several coronaviruses, including SARS-CoV and MERS-CoV. Our findings reveal a previously unrecognized antiviral role of the TOM1-TOLLIP complex and demonstrate how coronaviruses evade this host defense, providing new insight into virus-host interactions and potential targets for antiviral therapies.
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