| Autor: |
Grin, Peter M., Baid, Kaushal, de Jesus, Hugo C.R., Kozarac, Nedim, Bell, Peter A., Jiang, Steven Z., Kappelhoff, Reinhild, Butler, Georgina S., Leborgne, Nathan G.F., Pan, Christina, Pablos, Isabel, Machado, Yoan, Vederas, John C., Kim, Hugh, Benarafa, Charaf, Banerjee, Arinjay, Overall, Christopher M. |
| Zdroj: |
Cell Reports; December 2024, Vol. 43 Issue: 12 |
| Abstrakt: |
SARS-CoV-2 3C-like protease (3CLproor Mpro) 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 3CLproexpression and viral replication. Unexpectedly, 3CLproand 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 3CLpro, which decreases in Gsdmd−/−Gsdme−/−mice. We identify new 3CLprocut-sites in GSDMD at LQ29↓30SS, which blocks pore formation by 3CLprocleavage at LH270↓N lying adjacent to the caspase activation site (NFLTD275↓G). Cleavage inactivation of GSDMD prevents excessive pore formation, thus countering antiviral pyroptosis and increasing 3CLprosecretion. Extracellular 3CLproretains activity in serum, dampens platelet activation and aggregation, and inactivates antiviral interferon-λ1. Thus, in countering gasdermin pore formation and pyroptosis in SARS-CoV-2 infection, 3CLprois secreted with extracellular pathological sequelae. |
| Databáze: |
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