| First Author | Grin PM | Year | 2024 |
| Journal | Cell Rep | Volume | 43 |
| Issue | 12 | Pages | 115080 |
| PubMed ID | 39673710 | Mgi Jnum | J:361354 |
| Mgi Id | MGI:7852029 | Doi | 10.1016/j.celrep.2024.115080 |
| Citation | Grin PM, et al. (2024) SARS-CoV-2 3CL(pro) (main protease) regulates caspase activation of gasdermin-D/E pores leading to secretion and extracellular activity of 3CL(pro). Cell Rep 43(12):115080 |
| abstractText | SARS-CoV-2 3C-like protease (3CL(pro) or M(pro)) cleaves the SARS-CoV-2 polyprotein and >300 intracellular host proteins to enhance viral replication. By lytic cell death following gasdermin (GSDM) pore formation in cell membranes, antiviral pyroptosis decreases 3CL(pro) expression and viral replication. Unexpectedly, 3CL(pro) and nucleocapsid proteins undergo unconventional secretion from infected cells via caspase-activated GSDMD/E pores in the absence of cell lysis. Bronchoalveolar lavage fluid of wild-type SARS-CoV-2-infected mice contains 3CL(pro), which decreases in Gsdmd(-/-)Gsdme(-/-) mice. We identify new 3CL(pro) cut-sites in GSDMD at LQ(29) downward arrow(30)SS, which blocks pore formation by 3CL(pro) cleavage at LH(270) downward arrowN lying adjacent to the caspase activation site (NFLTD(275) downward arrowG). Cleavage inactivation of GSDMD prevents excessive pore formation, thus countering antiviral pyroptosis and increasing 3CL(pro) secretion. Extracellular 3CL(pro) retains activity in serum, dampens platelet activation and aggregation, and inactivates antiviral interferon-lambda1. Thus, in countering gasdermin pore formation and pyroptosis in SARS-CoV-2 infection, 3CL(pro) is secreted with extracellular pathological sequelae. |
