Norovirus MLKL-like protein initiates cell death to induce viral egress.

Autor: Wang G; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Zhang D; Department of Biochemistry, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA., Orchard RC; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Hancks DC; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Dustin.Hancks@utsouthwestern.edu., Reese TA; Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Tiffany.Reese@utsouthwestern.edu.; Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Tiffany.Reese@utsouthwestern.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2023 Apr; Vol. 616 (7955), pp. 152-158. Date of Electronic Publication: 2023 Mar 29.
DOI: 10.1038/s41586-023-05851-w
Abstrakt: Non-enveloped viruses require cell lysis to release new virions from infected cells, suggesting that these viruses require mechanisms to induce cell death. Noroviruses are one such group of viruses, but there is no known mechanism that causes norovirus infection-triggered cell death and lysis 1-3 . Here we identify a molecular mechanism of norovirus-induced cell death. We found that the norovirus-encoded NTPase NS3 contains an N-terminal four-helix bundle domain homologous to the membrane-disruption domain of the pseudokinase mixed lineage kinase domain-like (MLKL). NS3 has a mitochondrial localization signal and thus induces cell death by targeting mitochondria. Full-length NS3 and an N-terminal fragment of the protein bound the mitochondrial membrane lipid cardiolipin, permeabilized the mitochondrial membrane and induced mitochondrial dysfunction. Both the N-terminal region and the mitochondrial localization motif of NS3 were essential for cell death, viral egress from cells and viral replication in mice. These findings suggest that noroviruses have acquired a host MLKL-like pore-forming domain to facilitate viral egress by inducing mitochondrial dysfunction.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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